Salts and crystal forms of omecamtiv mecarbil

ABSTRACT

Provided herein are free base crystalline forms, crystalline salts, and an amorphous salts of omecamtiv mecarbil.

TECHNICAL FIELD OF INVENTION

The present disclosure relates to salts and crystal forms of omecamtivmecarbil, pharmaceutical compositions thereof and methods of using thesame.

BACKGROUND

The cardiac sarcomere is the basic unit of muscle contraction in theheart. The cardiac sarcomere is a highly ordered cytoskeletal structurecomposed of cardiac muscle myosin, actin and a set of regulatoryproteins. The discovery and development of small molecule cardiac musclemyosin activators would lead to promising treatments for acute andchronic heart failure and dilated cardiomyopathy (DCM) and conditionsassociated with left and/or right ventricular systolic dysfunction orsystolic reserve. Cardiac muscle myosin is the cytoskeletal motorprotein in the cardiac muscle cell. It is directly responsible forconverting chemical energy into the mechanical force, resulting incardiac muscle contraction.

Current positive inotropic agents, such as beta-adrenergic receptoragonists or inhibitors of phosphodiesterase activity, increase theconcentration of intracellular calcium, thereby increasing cardiacsarcomere contractility. However, the increase in calcium levelsincrease the velocity of cardiac muscle contraction and shortenssystolic ejection time, which has been linked to potentiallylife-threatening side effects. In contrast, cardiac muscle myosinactivators work by a mechanism that directly stimulates the activity ofthe cardiac muscle myosin motor protein, without increasing theintracellular calcium concentration. They accelerate the rate-limitingstep of the myosin enzymatic cycle and shift it in favor of theforce-producing state. Rather than increasing the velocity of cardiaccontraction, this mechanism instead lengthens the systolic ejectiontime, which results in increased cardiac muscle contractility andcardiac output in a potentially more oxygen-efficient manner.

Omecamtiv mecarbil is a first in class direct activator of cardiacmyosin, the motor protein that causes cardiac contraction. It is beingevaluated as a potential treatment of heart failure in both intravenousand oral formulations with the goal of establishing a new continuum ofcare for patients in both the in-hospital and outpatient settings.Omecamtiv mecarbil has a structure of

(see, e.g., U.S. Pat. No. 7,507,735), and has alternatively beenreferred to as methyl4-(2-fluoro-3-(3-(6-methylpyridin-3-yl)ureido)benzyl)piperazine-1-carboxylate,AMG 423, and CK 1827452.

There is a need for various new salt and crystalline forms of omecamtivmecarbil with different chemical and physical stabilities, andformulations and uses of the same.

SUMMARY

Provided herein are salts and crystal forms of omecamtiv mecarbil,including free base crystalline forms, crystalline salts and amorphoussalt forms of omecamtiv mecarbil. In some embodiments, provided hereinis the omecamtiv mecarbil free base crystalline form III. In someembodiments, provided herein is the omecamtiv mecarbil free basecrystalline form IV. In some embodiments, provided herein is theomecamtiv mecarbil free base crystalline form V. In some embodiments,provided herein is the omecamtiv mecarbil free base crystalline form VI.In some embodiments, provided herein is the omecamtiv mecarbil free basecrystalline form VII. In some embodiments, provided herein is theomecamtiv mecarbil amorphous hydrochloride salt. In some embodiments,provided herein is the omecamtiv mecarbil ethane sulfonate crystallinesalt. In some embodiments, provided herein is the omecamtiv mecarbilbis-fumarate crystalline salt form A. In some embodiments, providedherein is the omecamtiv mecarbil bis-fumarate crystalline salt form B.In some embodiments, provided herein is the omecamtiv mecarbilbis-fumarate crystalline salt form C. In some embodiments, providedherein is the omecamtiv mecarbil mono-fumarate crystalline salt form D.In some embodiments, provided herein is the omecamtiv mecarbilbis-maleate crystalline salt. In some embodiments, provided herein isthe omecamtiv mecarbil bis-malonate crystalline salt. In someembodiments, provided herein is the omecamtiv mecarbil mesylatecrystalline salt form A. In some embodiments, provided herein is theomecamtiv mecarbil bis-mesylate crystalline salt form B. In someembodiments, provided herein is the omecamtiv mecarbilbis-naphthalate-2-sulfonate crystalline salt. In some embodiments,provided herein is the omecamtiv mecarbil mono-napadisylate crystallinesalt. In some embodiments, provided herein is the omecamtiv mecarbilnicotinate crystalline salt. In some embodiments, provided herein is theomecamtiv mecarbil oxalate crystalline salt form A. In some embodiments,provided herein is the omecamtiv mecarbil oxalate crystalline salt formB. In some embodiments, provided herein is the omecamtiv mecarbilsalicylate crystalline salt. In some embodiments, provided herein is theomecamtiv mecarbil hemi-succinate crystalline salt. In some embodiments,provided herein is the omecamtiv mecarbil bis-sulfate crystalline saltform A. In some embodiments, provided herein is the omecamtiv mecarbilbis-sulfate crystalline salt form B. In some embodiments, providedherein is the omecamtiv mecarbil bis-sulfate crystalline salt form C. Insome embodiments, provided herein is the omecamtiv mecarbil sulfatecrystalline salt form D. In some embodiments, provided herein is theomecamtiv mecarbil 2-hydroxyethane sulfonate crystalline salt. In someembodiments, provided herein is the omecamtiv mecarbil bis-tartratecrystalline salt form A. In some embodiments, provided herein is theomecamtiv mecarbil bis-tartrate crystalline salt form B. In someembodiments, provided herein is the omecamtiv mecarbil bis-tartratecrystalline salt form C. In some embodiments, provided herein is theomecamtiv mecarbil mono-tartrate crystalline salt form D.

Also provided are pharmaceutical compositions comprising a salt orcrystal form of omecamtiv mecarbil as disclosed herein and apharmaceutically acceptable excipient.

Further provided are methods of treating heart failure in a subject inneed thereof comprising administering to the subject a salt or crystalform of omecamtiv mecarbil as disclosed herein in an amount effective totreat heart failure.

BRIEF DESCRIPTION OF FIGURES

FIG. 1 depicts an X-ray powder diffraction (“XRPD”) pattern of the freebase crystalline form III.

FIG. 2 depicts a differential scanning calorimetry (“DSC”) thermographof the free crystalline form III.

FIG. 3 depicts a thermogravimetric analysis (“TGA”) trace of the freebase crystalline form III.

FIG. 4 depicts an XRPD pattern of the free base crystalline form IV.

FIG. 5 depicts a DSC thermograph of the free base crystalline form IV.

FIG. 6 depicts a TGA trace of the free base crystalline form IV.

FIG. 7 depicts an XRPD pattern of the free base crystalline form V.

FIG. 8 depicts a DSC thermograph of the free base crystalline form V.

FIG. 9 depicts a TGA trace of the free base crystalline form V.

FIG. 10 depicts an XRPD pattern of the free base crystalline form VI.

FIG. 11 depicts a DSC thermograph of the free base crystalline form VI.

FIG. 12 depicts an XRPD pattern of the free base crystalline form VII.

FIG. 13 depicts an XRPD pattern overlay of the free base crystallineforms I-VII.

FIG. 14 depicts an XRPD pattern of the amorphous hydrochloride salt.

FIG. 15 depicts a DSC thermograph of the amorphous hydrochloride saltindicating a Tg of ˜149.16° C.

FIG. 16 depicts a TGA trace of the amorphous hydrochloride saltindicating a weight loss of ˜7.9% from ˜26° C. to 160° C.

FIG. 17 depicts a moisture sorption profile of the amorphoushydrochloride salt indicating a weight gain of ˜11% by 50% RH thenweight loss due to crystallization to Form A up to 95% RH.

FIG. 18 depicts an XRPD pattern of the ethane sulfonate crystallinesalt.

FIG. 19 depicts a thermal gravimetric/differential thermal analysis(“TG/DTA”) thermograph of the ethane sulfonate crystalline salt.

FIG. 20 depicts an XRPD pattern of the bis-fumarate crystalline saltform A.

FIG. 21 depicts a TGA trace of the bis-fumarate crystalline salt form A.

FIG. 22 depicts an XRPD pattern of the bis-fumarate crystalline saltform B.

FIG. 23 depicts a TGA trace of the bis-fumarate crystalline salt form B.

FIG. 24 depicts an XRPD pattern of the bis-fumarate crystalline saltform C.

FIG. 25 depicts a TGA trace of the bis-fumarate crystalline salt form C.

FIG. 26 depicts an XRPD pattern of the mono-fumarate crystalline saltform D.

FIG. 27 depicts a DSC thermograph of the mono-fumarate crystalline saltform D.

FIG. 28 depicts a TGA trace of the mono-fumarate crystalline salt formD.

FIG. 29 depicts an XRPD pattern overlay of the fumarate crystallinesalts A-D.

FIG. 30 depicts an XRPD pattern of the bis-maleate crystalline salt.

FIG. 31 depicts a DSC thermograph of the bis-maleate crystalline salt.

FIG. 32 depicts a TGA trace of the bis-maleate crystalline salt.

FIG. 33 depicts an XRPD pattern of the bis-malonate crystalline salt.

FIG. 34 depicts a TGA trace of the bis-malonate crystalline salt.

FIG. 35 depicts an XRPD pattern of the mesylate crystalline salt form A.

FIG. 36 depicts a TGA trace of the mesylate crystalline salt form A.

FIG. 37 depicts an XRPD of the bis-mesylate crystalline salt form B.

FIG. 38 depicts a thermal gravimetric/differential thermal analysis(“TG/DTA”) of the bis-mesylate crystalline salt form B.

FIG. 39 depicts an XRPD pattern overlay of the mesylate crystalline saltform A and B.

FIG. 40 depicts an XRPD pattern of the bis-naphthalate-2-sulfonatecrystalline salt.

FIG. 41 depicts a TG/DTA of the bis-naphthalate-2-sulfonate crystallinesalt.

FIG. 42 depicts an XRPD pattern of the mono-napadisylate crystallinesalt.

FIG. 43 depicts a DSC thermograph of the mono-napadisylate crystallinesalt.

FIG. 44 depicts a TGA trace of the mono-napadisylate crystalline salt.

FIG. 45 depicts an XRPD pattern of the nicotinate crystalline salt.

FIG. 46 depicts a TG/DTA of the nicotinate crystalline salt.

FIG. 47 depicts an XRPD pattern of the oxalate crystalline salt form A.

FIG. 48 depicts a DSC thermograph of the oxalate crystalline salt formA.

FIG. 49 depicts a TGA trace of the oxalate crystalline salt form A.

FIG. 50 depicts an XRPD pattern of the oxalate crystalline salt form B.

FIG. 51 depicts a TGA trace of the oxalate crystalline salt form B.

FIG. 52 depicts an XRPD overlay of the oxalate crystalline salt forms Aand B.

FIG. 53 depicts an XRPD pattern of the salicylate crystalline salt.

FIG. 54 depicts a TG/DTA of the salicylate crystalline salt.

FIG. 55 depicts XRPD patterns of the hemi-succinate crystalline saltsoverlaid.

FIG. 56 depicts a DSC thermograph of the hemi-succinate crystallinesalt.

FIG. 57 depicts an XRPD patter of the bis-sulfate crystalline salt formA.

FIG. 58 depicts an XRPD pattern of the bis-sulfate crystalline salt formB.

FIG. 59 depicts a TGA trace of the bis-sulfate crystalline salt form B.

FIG. 60 depicts an XRPD pattern of the bis-sulfate crystalline salt formC.

FIG. 61 depicts a TGA trace of the bis-sulfate crystalline salt form C.

FIG. 62 depicts an XRPD pattern of the sulfate crystalline salt form D.

FIG. 63 depicts a TG/DTA of the sulfate crystalline salt form D.

FIG. 64 depicts an XRPD pattern overlay of the sulfate crystalline saltforms A-D.

FIG. 65 depicts an XRPD pattern of the 2-hydroxyethane sulfonatecrystalline salt.

FIG. 66 depicts a TG/DTA of the 2-hydroxyethane sulfonate crystallinesalt.

FIG. 67 depicts an XRPD pattern of the bis-tartrate crystalline saltform A.

FIG. 68 depicts a TGA trace of the bis-tartrate crystalline salt form A.

FIG. 69 depicts an XRPD pattern of the bis-tartrate crystalline saltform B.

FIG. 70 depicts a TGA trace of the bis-tartrate crystalline salt form B.

FIG. 71 depicts an XRPD pattern of the bis-tartrate crystalline saltform C.

FIG. 72 depicts a TGA trace of the bis-tartrate crystalline salt form C.

FIG. 73 depicts an XRPD pattern of the mono-tartrate crystalline saltform D.

FIG. 74 depicts a TGA trace of the mono-tartrate crystalline salt formD.

FIG. 75 depicts an XRPD pattern overlay of the tartrate crystalline saltform A-D.

DETAILED DESCRIPTION

The present disclosure provides salts and crystal forms of omecamtivmecarbil.

Embodiments of the free base crystalline forms, crystalline salts andamorphous salt of omecamtiv mecarbil can be characterized by one or moreof the parameters described in further detail below.

Free Base Crystalline Forms of Omecamtiv Mecarbil

Provided herein are free base crystalline forms of omecamtiv mecarbil.In some embodiments, the free base crystalline forms of omecamtivmecarbil can be nonionic forms of omecamtiv mecarbil. In someembodiments, the free base crystalline forms III-VII of omecamtivmecarbil can be anhydrous. The free base crystalline forms I and II ofomecamtiv mecarbil depicted in FIG. 13 are prepared and discussed indetail in Morrison et. al, Organic Process Research & Development, 2015,19, 1842-1848.

Free Base Crystalline Form III

Free base crystalline form III of omecamtiv mecarbil can becharacterized by an X-ray powder diffraction pattern, obtained as setforth in the Examples, having peaks at about 9.50, 19.06, and 23.01±0.2°2θ using Cu Kα radiation. Free base crystalline form III optionally canbe further characterized by an X-ray powder diffraction pattern havingadditional peaks at about 14.27, 15.25, 16.10, 17.78, and 23.87±0.2° 2θusing Cu Kα radiation. Free base crystalline form III optionally can befurther characterized by an X-ray powder diffraction pattern havingadditional peaks at about 7.91, 20.65, 28.11, 31.01, 31.95, and32.34±0.2° 2θ using Cu Kα radiation. Free base crystalline form IIIoptionally can be characterized by an X-ray powder diffraction patternhaving peaks shown in Table 1 set forth in the Examples. In someembodiments, free base crystalline form III has an X-ray powderdiffraction pattern substantially as shown in FIG. 1, wherein by“substantially” is meant that the reported peaks can vary by about±0.2°. It is well known in the field of XRPD that while relative peakheights in spectra are dependent on a number of factors, such as samplepreparation and instrument geometry, peak positions are relativelyinsensitive to experimental details.

Differential scanning calorimetry (DSC) thermographs were obtained, asset forth in the Examples, for free base crystalline form III. The DSCcurve indicates an endothermic transition at about 186° C.±3° C. Thus,in some embodiments, free base crystalline form III can be characterizedby a DSC thermograph having a decomposition endotherm with an onset in arange of about 175° C. to about 190° C. For example, in some embodimentsfree base crystalline form III is characterized by DSC, as shown in FIG.2.

Free base crystalline form III also can be characterized bythermogravimetric analysis (TGA). Thus, free base crystalline form IIIcan be characterized by a weight loss in a range of about 0% to about 1%with an onset temperature in a range of about 25° C. to about 100° C.For example, free base crystalline form III can be characterized by aweight loss of about 0%, up to about 150° C. In some embodiments, freebase crystalline form III has a thermogravimetric analysis substantiallyas depicted in FIG. 3, wherein by “substantially” is meant that thereported TGA features can vary by about ±5° C.

Free Base Crystalline Form IV

Free base crystalline form IV of omecamtiv mecarbil can be characterizedby an X-ray powder diffraction pattern, obtained as set forth in theExamples, having peaks at about 5.18, 10.35, 14.84, 15.54, 18.10, and19.92±0.2° 2θ using Cu Kα radiation. Free base crystalline form IVoptionally can be further characterized by an X-ray powder diffractionpattern having additional peaks at about 14.21, 20.62, 20.77, 22.86,24.05, 24.36, 27.81, and 29.42±0.2° 2θ using Cu Kα radiation. Free basecrystalline form IV optionally can be further characterized by an X-raypowder diffraction pattern having additional peaks at about 7.42, 7.70,21.70, 22.40, 23.09, 25.20, 25.72, 27.40, 28.18, 28.63, 28.98, and30.51±0.2° 2θ using Cu Kα radiation. Free base crystalline form IV canbe characterized by an X-ray powder diffraction pattern having peaksshown in Table 2 set forth in the Examples. In some embodiments, freebase crystalline form IV has an X-ray powder diffraction patternsubstantially as shown in FIG. 4, wherein by “substantially” is meantthat the reported peaks can vary by about ±0.2°.

Differential scanning calorimetry (DSC) thermographs were obtained, asset forth in the Examples, for free base crystalline form IV. The DSCcurve indicates an endothermic transition at about 185° C.±3° C. Thus,in some embodiments, free base crystalline form IV can be characterizedby a DSC thermograph having a decomposition endotherm with an onset in arange of about 175° C. to about 190° C. For example, in some embodimentsfree base crystalline form IV is characterized by DSC, as shown in FIG.5.

Free base crystalline form IV also can be characterized bythermogravimetric analysis (TGA). Thus, free base crystalline form IVcan be characterized by a weight loss in a range of about 0% to about 1%with an onset temperature in a range of about 25° C. to about 100° C.For example, free base crystalline form IV can be characterized by aweight loss of about 0%, up to about 150° C. In some embodiments, freebase crystalline form IV has a thermogravimetric analysis substantiallyas depicted in FIG. 6, wherein by “substantially” is meant that thereported TGA features can vary by about ±5° C.

Free Base Crystalline Form V

Free base crystalline form V of omecamtiv mecarbil can be characterizedby an X-ray powder diffraction pattern, obtained as set forth in theExamples, having peaks at about 7.38, 8.56, 9.14, and 18.28±0.2° 2θusing Cu Kα radiation. Free base crystalline form V optionally can befurther characterized by an X-ray powder diffraction pattern havingadditional peaks at about 8.93, 10.03, 10.73, 11.71, 13.69, 15.08,16.85, 17.85, 18.86, 20.05, 20.72, 21.74, 23.56, 24.03, 26.23, and27.62±0.2° 2θ using Cu Kα radiation. Free base crystalline form Voptionally can be further characterized by an X-ray powder diffractionpattern having additional peaks at about 5.40, 16.04, 22.83, 25.45,26.23, 27.62, 28.58, 29.85, 32.10, and 33.37±0.2° 2θ using Cu Kαradiation. Free base crystalline form V can be characterized by an X-raypowder diffraction pattern having peaks shown in Table 3 set forth inthe Examples. In some embodiments, free base crystalline form V has anX-ray powder diffraction pattern substantially as shown in FIG. 7,wherein by “substantially” is meant that the reported peaks can vary byabout ±0.2°.

Differential scanning calorimetry (DSC) thermographs were obtained, asset forth in the Examples, for Form V. The DSC curve indicates anendothermic transition at about 185° C.±3° C. Thus, in some embodiments,free base crystalline form V can be characterized by a DSC thermographhaving a decomposition endotherm with an onset in a range of about 175°C. to about 190° C. For example, in some embodiments free basecrystalline form V is characterized by DSC, as shown in FIG. 8.

Free base crystalline form V also can be characterized bythermogravimetric analysis (TGA). Thus, free base crystalline form V canbe characterized by a weight loss in a range of about 2% to about 6%with an onset temperature in a range of about 25° C. to about 100° C.For example, free base crystalline form V can be characterized by aweight loss of about 4.2%, up to about 150° C. In some embodiments, freebase crystalline form V has a thermogravimetric analysis substantiallyas depicted in FIG. 9, wherein by “substantially” is meant that thereported TGA features can vary by about ±5° C.

Free Base Crystalline Form VI

Free base crystalline form VI of omecamtiv mecarbil can be characterizedby an X-ray powder diffraction pattern, obtained as set forth in theExamples, having peaks at about 9.07, 16.67, 18.18, 19.70, 20.89, and21.28±0.2° 2θ using Cu Kα radiation. Free base crystalline form VIoptionally can be further characterized by an X-ray powder diffractionpattern having additional peaks at about 15.88, 17.81, 18.80, 23.72,24.26, 26.80, 27.59, and 29.82±0.2° 2θ using Cu Kα radiation. Free basecrystalline form VI optionally can be further characterized by an X-raypowder diffraction pattern having additional peaks at about 14.28,20.23, 26.19, and 28.90±0.2° 2θ using Cu Kα radiation. Free basecrystalline form VI can be characterized by an X-ray powder diffractionpattern having peaks shown in Table 4 set forth in the Examples. In someembodiments, free base crystalline form VI has an X-ray powderdiffraction pattern substantially as shown in FIG. 10, wherein by“substantially” is meant that the reported peaks can vary by about±0.2°.

Differential scanning calorimetry (DSC) thermographs were obtained, asset forth in the Examples, for Form VI. The DSC curve indicates anendothermic transition at about 185° C.±3° C. Thus, in some embodiments,free base crystalline form VI can be characterized by a DSC thermographhaving a decomposition endotherm with an onset in a range of about 175°C. to about 190° C. For example, in some embodiments free basecrystalline form VI is characterized by DSC, as shown in FIG. 11.

Free Base Crystalline Form VII

Free base crystalline form VII of omecamtiv mecarbil can becharacterized by an X-ray powder diffraction pattern, obtained as setforth in the Examples, having peaks at about 8.40, 8.71, 13.08, 15.66,and 19.61±0.2° 2θ using Cu Kα radiation. Free base crystalline form VIIoptionally can be further characterized by an X-ray powder diffractionpattern having additional peaks at about 4.37, 16.83, 18.92, 20.32,20.49, 22.26, 24.21, and 25.41±0.2° 2θ using Cu Kα radiation. Free basecrystalline form VII optionally can be further characterized by an X-raypowder diffraction pattern having additional peaks at about 7.84, 10.81,21.61, 23.22, 23.46, 27.58, 29.53, 30.13, and 31.32±0.2° 2θ using Cu Kαradiation. Free base crystalline form VII can be characterized by anX-ray powder diffraction pattern having peaks shown in Table 5 set forthin the Examples. In some embodiments, the free base crystalline form VIIhas an X-ray powder diffraction pattern substantially as shown in FIG.12, wherein by “substantially” is meant that the reported peaks can varyby about ±0.2°.

Crystalline Salts of Omecamtiv Mecarbil

Provided herein are various crystalline salts of omecamtiv mecarbil.Specifically provided are crystalline salts of omecamtiv mecarbil,wherein the salt is an ethane sulfonate salt, a fumarate salt, a maleatesalt, a malonate salt, a mesylate salt, a naphthalate-2-sulfonate salt,a napadisylate salt, a nicotinate salt, an oxalate salt, a salicylatesalt, a succinate salt, a sulfate salt, a hydroxyethane sulfonate salt,or a tartrate salt.

Ethane Sulfonate Crystalline Salt

The ethane sulfonate crystalline salt of omecamtiv mecarbil can becharacterized by an X-ray powder diffraction pattern, obtained as setforth in the Examples, having peaks at about 8.61, 16.14, 16.76, 16.9720.73, 20.96, 25.95, and 26.30±0.2° 2θ using Cu Kα radiation. The ethanesulfonate crystalline salt optionally can be further characterized by anX-ray powder diffraction pattern having additional peaks at about 17.23,18.35, 19.20, 20.27, 23.73, 25.24, and 27.09±0.2° 2θ using Cu Kαradiation. The ethane sulfonate crystalline salt can be characterized byan X-ray powder diffraction pattern having peaks shown in Table 7 setforth in the Examples. In some embodiments, the ethane sulfonatecrystalline salt has an X-ray powder diffraction pattern substantiallyas shown in FIG. 18, wherein by “substantially” is meant that thereported peaks can vary by about ±0.2°. In some embodiments, ethanesulfonate crystalline salt has an TG/DTA substantially as shown in FIG.19.

Bis-Fumarate Crystalline Salt Form A

Bis-fumarate crystalline salt form A of omecamtiv mecarbil can becharacterized by an X-ray powder diffraction pattern, obtained as setforth in the Examples, having peaks at about 5.64, 15.76, 22.03, and23.87±0.2° 2θ using Cu Kα radiation. Bis-fumarate crystalline salt formA optionally can be further characterized by an X-ray powder diffractionpattern having additional peaks at about 16.80, 21.55, 21.87, 23.61,23.87, 26.01, and 27.20±0.2° 2θ using Cu Kα radiation. Bis-fumaratecrystalline salt form A optionally can be further characterized by anX-ray powder diffraction pattern having additional peaks at about 10.80,12.04, 15.76, 16.40, 17.94, 18.32, 19.87, 20.61, 22.88, 27.86, 32.73,and 36.54±0.2° 2θ using Cu Kα radiation. Bis-fumarate crystalline saltform A can be characterized by an X-ray powder diffraction patternhaving peaks shown in Table 8 set forth in the Examples. In someembodiments, the bis-fumarate crystalline salt form A has an X-raypowder diffraction pattern substantially as shown in FIG. 20, wherein by“substantially” is meant that the reported peaks can vary by about±0.2°.

Bis-fumarate crystalline salt form A also can be characterized bythermogravimetric analysis (TGA). Thus, bis-fumarate crystalline saltform A can be characterized by a weight loss in a range of about 6% toabout 10% with an onset temperature in a range of about 25° C. to about100° C. For example, bis-fumarate crystalline salt form A can becharacterized by a weight loss of about 7.9%, up to about 150° C. Insome embodiments, bis-fumarate crystalline salt form A has athermogravimetric analysis substantially as depicted in FIG. 21, whereinby “substantially” is meant that the reported TGA features can vary byabout ±5° C.

Bis-Fumarate Crystalline Salt Form B

Bis-fumarate crystalline salt form B of omecamtiv mecarbil can becharacterized by an X-ray powder diffraction pattern, obtained as setforth in the Examples, having peaks at about 5.68, 6.11, 13.13, 18.08,and 22.47±0.2° 2θ using Cu Kα radiation. Bis-fumarate crystalline saltform B optionally can be further characterized by an X-ray powderdiffraction pattern having additional peaks at about 9.69, 11.43, 12.92,15.95, 20.81, 22.95, 26.04, 27.01, and 28.43±0.2° 2θ using Cu Kαradiation. Bis-fumarate crystalline salt form B optionally can befurther characterized by an X-ray powder diffraction pattern havingadditional peaks at about 19.52, 24.53, 31.37, 32.32, 34.89, 35.89, and37.16±0.2° 2θ using Cu Kα radiation. Bis-fumarate crystalline salt formB optionally can be characterized by an X-ray powder diffraction patternhaving peaks shown in Table 9 set forth in the Examples. In someembodiments, the bis-fumarate crystalline salt form B has an X-raypowder diffraction pattern substantially as shown in FIG. 22, wherein by“substantially” is meant that the reported peaks can vary by about±0.2°.

Bis-fumarate crystalline salt form B also can be characterized bythermogravimetric analysis (TGA). Thus, bis-fumarate crystalline saltform B can be characterized by a weight loss in a range of about 4% toabout 8% with an onset temperature in a range of about 25° C. to about100° C. For example, bis-fumarate crystalline salt form B can becharacterized by a weight loss of about 5.6%, up to about 150° C. Insome embodiments, bis-fumarate crystalline salt form B has athermogravimetric analysis substantially as depicted in FIG. 23, whereinby “substantially” is meant that the reported TGA features can vary byabout ±5° C.

Bis-Fumarate Crystalline Salt Form C

Bis-fumarate crystalline salt form C of omecamtiv mecarbil can becharacterized by an X-ray powder diffraction pattern, obtained as setforth in the Examples, having peaks at about 5.88, 18.79, 25.41, and26.86±0.2° 2θ using Cu Kα radiation. Bis-fumarate crystalline salt formC optionally can be further characterized by an X-ray powder diffractionpattern having additional peaks at about 12.74, 13.56, 17.15, 17.63,20.29, 21.47, 21.77, 22.21, 22.92, 23.58, 24.15, 25.41, 26.78, and27.83±0.2° 2θ using Cu Kα radiation. Bis-fumarate crystalline salt formC can be characterized by an X-ray powder diffraction pattern havingpeaks shown in Table 10 set forth in the Examples. In some embodiments,the bis-fumarate crystalline salt form C has an X-ray powder diffractionpattern substantially as shown in FIG. 24, wherein by “substantially” ismeant that the reported peaks can vary by about ±0.2°.

Bis-fumarate crystalline salt form C also can be characterized bythermogravimetric analysis (TGA). Thus, bis-fumarate crystalline saltform C can be characterized by a weight loss in a range of about 6% toabout 10% with an onset temperature in a range of about 25° C. to about100° C. For example, bis-fumarate crystalline salt form C can becharacterized by a weight loss of about 8.4%, up to about 150° C. Insome embodiments, bis-fumarate crystalline salt form C has athermogravimetric analysis substantially as depicted in FIG. 25, whereinby “substantially” is meant that the reported TGA features can vary byabout ±5° C. This weight loss was determined to be water via KarlFischer (KF) analysis. KF analysis shows that the water content ofbis-fumarate crystalline salt form C can be about 8.4%, corresponding toa trihydrate.

Mono-Fumarate Crystalline Salt Form D

Mono-fumarate crystalline salt form D of omecamtiv mecarbil can becharacterized by an X-ray powder diffraction pattern, obtained as setforth in the Examples, having peaks at about 8.01, 15.20, and 20.02±0.2°2θ using Cu Kα radiation. Mono-fumarate crystalline salt form Doptionally can be further characterized by an X-ray powder diffractionpattern having additional peaks at about 12.11, 12.67, 14.46, 16.01,16.57, 17.04, 17.63, 20.51, 21.75, 22.86, 24.25, 24.97, 25.84, 26.17,27.10, 27.97, and 29.21±0.2° 2θ using Cu Kα radiation. Mono-fumaratecrystalline salt form D can be characterized by an X-ray powderdiffraction pattern having peaks shown in Table 11 set forth in theExamples. In some embodiments, mono-fumarate crystalline salt form D hasan X-ray powder diffraction pattern substantially as shown in FIG. 26,wherein by “substantially” is meant that the reported peaks can vary byabout ±0.2°.

Differential scanning calorimetry (DSC) thermographs were obtained, asset forth in the Examples, for mono-fumarate crystalline salt form D.The DSC curve indicates an endothermic transition at about 125° C.±3° C.Thus, in some embodiments, mono-fumarate crystalline salt form D can becharacterized by a DSC thermograph having a decomposition endotherm withan onset in a range of about 110° C. to about 130° C. For example, insome embodiments mono-fumarate crystalline salt form D is characterizedby DSC, as shown in FIG. 27.

Mono-fumarate crystalline salt form D also can be characterized bythermogravimetric analysis (TGA). Thus, mono-fumarate crystalline saltform D can be characterized by a weight loss in a range of about 5% toabout 9% with an onset temperature in a range of about 25° C. to about100° C. For example, mono-fumarate crystalline salt form D can becharacterized by a weight loss of about 6.7%, up to about 150° C. Insome embodiments, mono-fumarate crystalline salt form D has athermogravimetric analysis substantially as depicted in FIG. 28, whereinby “substantially” is meant that the reported TGA features can vary byabout ±5° C.

Bis-Maleate Crystalline Salt

The bis-maleate crystalline salt of omecamtiv mecarbil can becharacterized by an X-ray powder diffraction pattern, obtained as setforth in the Examples, having peaks at about 9.97, 15.31, 16.04, and26.96±0.2° 2θ using Cu Kα radiation. The bis-maleate crystalline saltoptionally can be further characterized by an X-ray powder diffractionpattern having additional peaks at about 10.56, 13.25, 15.53, 16.38,17.44, 17.70, 18.17, 19.00, 20.13, 21.47, 22.31, 22.44, 24.38, 24.64,25.66, 26.66, and 27.83±0.2° 2θ using Cu Kα radiation. The bis-maleatecrystalline salt optionally can be further characterized by an X-raypowder diffraction pattern having additional peaks at 4.99, 14.83,17.10, 22.02, 28.55, 30.76, 32.01, 34.39, and 34.51±0.2° 2θ using Cu Kαradiation. The bis-maleate crystalline salt can be characterized by anX-ray powder diffraction pattern having peaks shown in Table 13 setforth in the Examples. In some embodiments, the bis-maleate crystallinesalt has an X-ray powder diffraction pattern substantially as shown inFIG. 30, wherein by “substantially” is meant that the reported peaks canvary by about ±0.2°.

Differential scanning calorimetry (DSC) thermographs were obtained, asset forth in the Examples, for the bis-maleate crystalline salt. The DSCcurve indicates an endothermic transition at about 190° C.±3° C. Thus,in some embodiments, the bis-maleate crystalline salt can becharacterized by a DSC thermograph having a decomposition endotherm withan onset in a range of about 160° C. to about 210° C. For example, insome embodiments the bis-maleate crystalline salt is characterized byDSC, as shown in Figure

The bis-maleate crystalline salt also can be characterized bythermogravimetric analysis (TGA). Thus, the bis-maleate crystalline saltcan be characterized by a weight loss in a range of about 0% to about 1%with an onset temperature in a range of about 25° C. to about 150° C.For example, the bis-maleate crystalline salt can be characterized by aweight loss of about 0%, up to about 150° C. In some embodiments, thebis-maleate crystalline salt has a thermogravimetric analysissubstantially as depicted in FIG. 32, wherein by “substantially” ismeant that the reported TGA features can vary by about ±5° C.

Bis-Malonate Crystalline Salt

The bis-malonate crystalline salt of omecamtiv mecarbil can becharacterized by an X-ray powder diffraction pattern, obtained as setforth in the Examples, having peaks at about 4.74, 11.37, 14.25, 15.13,18.29, 20.14, 23.87, 27.78, and 28.01±0.2° 2θ using Cu Kα radiation. Thebis-malonate crystalline salt optionally can be further characterized byan X-ray powder diffraction pattern having additional peaks at about9.30, 13.73, 16.45, 16.83, 18.08, 18.88, 19.54, 20.77, 21.21, 23.32,24.67, 26.51, 27.59, and 28.90±0.2° 2θ using Cu Kα radiation. Thebis-malonate crystalline salt optionally can be further characterized byan X-ray powder diffraction pattern having additional peaks at about15.69, 25.72, 30.18, 33.70, 34.19±0.2° 2θ using Cu Kα radiation. Thebis-malonate crystalline salt can be characterized by an X-ray powderdiffraction pattern having peaks shown in Table 14 set forth in theExamples. In some embodiments, the bis-malonate crystalline salt has anX-ray powder diffraction pattern substantially as shown in FIG. 33,wherein by “substantially” is meant that the reported peaks can vary byabout ±0.2°.

The bis-malonate crystalline salt also can be characterized bythermogravimetric analysis (TGA). Thus, the bis-malonate crystallinesalt can be characterized by a weight loss in a range of about 0% toabout 1% with an onset temperature in a range of about 25° C. to about140° C. For example, the bis-malonate crystalline salt can becharacterized by a weight loss of about 0%, up to about 140° C. In someembodiments, the bis-malonate crystalline salt has a thermogravimetricanalysis substantially as depicted in FIG. 34, wherein by“substantially” is meant that the reported TGA features can vary byabout ±5° C.

Mesylate Crystalline Salt Form A

Mesylate crystalline salt form A of omecamtiv mecarbil can becharacterized by an X-ray powder diffraction pattern, obtained as setforth in the Examples, having peaks at about 4.02, 4.87, 15.21, 15.86,20.53, and 24.39±0.2° 2θ using Cu Kα radiation. Mesylate crystallinesalt form A optionally can be further characterized by an X-ray powderdiffraction pattern having additional peaks at about 7.79, 11.61, 16.51,17.57, 18.42, 19.26, 21.55, 23.17, 25.51, 26.38, and 27.63±0.2° 2θ usingCu Kα radiation. Mesylate crystalline salt form A can be characterizedby an X-ray powder diffraction pattern having peaks shown in Table 15set forth in the Examples. In some embodiments, mesylate crystallinesalt form A has an X-ray powder diffraction pattern substantially asshown in FIG. 35, wherein by “substantially” is meant that the reportedpeaks can vary by about ±0.2°.

Mesylate crystalline salt form A also can be characterized bythermogravimetric analysis (TGA). Thus, mesylate crystalline salt form Acan be characterized by a weight loss in a range of about 0% to about 2%with an onset temperature in a range of about 25° C. to about 175° C.For example, mesylate crystalline salt form A can be characterized by aweight loss of about 1.0%, up to about 200° C. In some embodiments,mesylate crystalline salt form A has a thermogravimetric analysissubstantially as depicted in FIG. 36, wherein by “substantially” ismeant that the reported TGA features can vary by about ±5° C.

Bis-Mesylate Crystalline Salt Form B

Bis-mesylate crystalline salt form B of omecamtiv mecarbil can becharacterized by an X-ray powder diffraction pattern, obtained as setforth in the Examples, having peaks at about 8.30, 8.94, 9.59, 12.15,14.37, 19.82, 20.29, 22.04, and 25.02±0.2° 2θ using Cu Kα radiation.Bis-mesylate crystalline salt form B optionally can be furthercharacterized by an X-ray powder diffraction pattern having additionalpeaks at about 11.66, 16.18, 16.64, 16.81, 17.07, 17.19, 17.41, 17.76,19.24, 20.66, 21.62, 22.39, 23.95, 24.60, 25.59, 25.89, 27.14, 27.35,27.41, and 29.45±0.2° 2θ using Cu Kα radiation. Bis-mesylate crystallinesalt form B optionally can be further characterized by an X-ray powderdiffraction pattern having additional peaks at about 10.78, 11.15,14.93, 15.36, 15.57, 23.54, 26.14, 26.49, 27.89, 28.86, 29.89, 31.11,32.47, 33.10, 33.51, 34.56±0.2° 2θ using Cu Kα radiation. Bis-mesylatecrystalline salt form B can be characterized by an X-ray powderdiffraction pattern having peaks shown in Table 16 set forth in theExamples. In some embodiments, bis-mesylate crystalline salt form B hasan X-ray powder diffraction pattern substantially as shown in FIG. 37,wherein by “substantially” is meant that the reported peaks can vary byabout ±0.2°. In some embodiments, bis-mesylate crystalline salt form Bhas a TG/DTA substantially as shown in FIG. 38.

Bis-Naphthalate-2-Sulfonate Crystalline Salt

The bis-naphthalate-2-sulfonate crystalline salt can be characterized byan X-ray powder diffraction pattern, obtained as set forth in theExamples, having peaks at about 4.49, 18.20, 18.62, 21.38, 21.52, and26.11±0.2° 2θ using Cu Kα radiation. The bis-naphthalate-2-sulfonatecrystalline salt optionally can be further characterized by an X-raypowder diffraction pattern having additional peaks at about 6.25, 6.65,13.44, 14.39, 14.92, 16.28, 18.90, 19.53, 20.82, 22.02, 22.43, 22.80,24.40, 25.16, 27.01, 29.67, 31.63, and 33.42±0.2° 2θ using Cu Kαradiation. The bis-naphthalate-2-sulfonate crystalline salt can becharacterized by an X-ray powder diffraction pattern having peaks shownin Table 18 set forth in the Examples. In some embodiments, thebis-naphthalate-2-sulfonate crystalline salt has an X-ray powderdiffraction pattern substantially as shown in FIG. 40, wherein by“substantially” is meant that the reported peaks can vary by about±0.2°. In some embodiments, bis-naphthalate-2-sulfonate crystalline salthas a TG/DTA substantially as shown in FIG. 41.

Mono-Napadisylate Crystalline Salt

The mono-napadisylate crystalline salt of omecamtiv mecarbil can becharacterized by an X-ray powder diffraction pattern, obtained as setforth in the Examples, having peaks at about 12.27, 15.75, 16.5, 17.83,19.94, 21.83, and 22.87±0.2° 2θ using Cu Kα radiation. Themono-napadisylate crystalline salt optionally can be furthercharacterized by an X-ray powder diffraction pattern having additionalpeaks at about 13.41, 14.57, 15.14, 18.82, 23.49, 24.34, and 25.26±0.2°2θ using Cu Kα radiation. The mono-napadisylate crystalline salt can becharacterized by an X-ray powder diffraction pattern having peaks shownin Table 19 set forth in the Examples. In some embodiments, themono-napadisylate crystalline salt has an X-ray powder diffractionpattern substantially as shown in FIG. 42, wherein by “substantially” ismeant that the reported peaks can vary by about ±0.2°.

Differential scanning calorimetry (DSC) thermographs were obtained, asset forth in the Examples, for the mono-napadisylate crystalline salt.The DSC curve indicates an endothermic transition at about 100° C.±3° C.Thus, in some embodiments, the mono-napadisylate crystalline salt can becharacterized by a DSC thermograph having a decomposition endotherm withan onset in a range of about 80° C. to about 115° C. For example, insome embodiments the mono-napadisylate crystalline salt is characterizedby DSC, as shown in FIG. 43.

The mono-napadisylate crystalline salt also can be characterized bythermogravimetric analysis (TGA). Thus, the mono-napadisylatecrystalline salt can be characterized by a weight loss in a range ofabout 4% to about 8% with an onset temperature in a range of about 20°C. to about 100° C. For example, the mono-napadisylate crystalline saltcan be characterized by a weight loss of about 5.8%, up to about 100° C.In some embodiments, the mono-napadisylate crystalline salt has athermogravimetric analysis substantially as depicted in FIG. 44, whereinby “substantially” is meant that the reported TGA features can vary byabout ±5° C.

Nicotinate Crystalline Salt

The nicotinate crystalline salt of omecamtiv mecarbil can becharacterized by an X-ray powder diffraction pattern, obtained as setforth in the Examples, having peaks at about 3.69, 8.55, 9.13, 16.70,16.84, 18.30, 19.99, 20.76, 23.43 24.83, and 25.95±0.2° 2θ using Cu Kαradiation. The nicotinate crystalline salt optionally can be furthercharacterized by an X-ray powder diffraction pattern having additionalpeaks at about 7.36, 10.01, 12.43, 14.74, 15.50, 17.62, 18.58, 19.59,20.34, 21.32, 22.03, 22.91, 23.87, 24.92, 25.40, 26.85, 26.94, 27.32,28.01, and 28.94±0.2° 2θ using Cu Kα radiation. The nicotinatecrystalline salt can be characterized by an X-ray powder diffractionpattern having peaks shown in Table 20 set forth in the Examples. Insome embodiments, the nicotinate crystalline salt has an X-ray powderdiffraction pattern substantially as shown in FIG. 45, wherein by“substantially” is meant that the reported peaks can vary by about±0.2°. In some embodiments, the nicotinate crystalline salt form D hasan TG/DTA substantially as shown in FIG. 46.

Oxalate Crystalline Salt Form A

Oxalate crystalline salt form A of omecamtiv mecarbil can becharacterized by an X-ray powder diffraction pattern, obtained as setforth in the Examples, having peaks at about 6.48, 13.01, and 23.82±0.2°2θ using Cu Kα radiation. Oxalate crystalline salt form A optionally canbe further characterized by an X-ray powder diffraction pattern havingadditional peaks at about 10.36, 11.85, 14.79, 15.35, 17.11, 19.23,19.91, 21.48, 22.07, 22.75, 25.70, 28.55, and 30.71±0.2° 2θ using Cu Kαradiation. Oxalate crystalline salt form A can be characterized by anX-ray powder diffraction pattern having peaks shown in Table 21 setforth in the Examples. In some embodiments, oxalate crystalline saltform A has an X-ray powder diffraction pattern substantially as shown inFIG. 47, wherein by “substantially” is meant that the reported peaks canvary by about ±0.2°.

Differential scanning calorimetry (DSC) thermographs were obtained, asset forth in the Examples, for oxalate crystalline salt form A. The DSCcurve indicates an endothermic transition at about 209° C.±3° C. Thus,in some embodiments, oxalate crystalline salt form A can becharacterized by a DSC thermograph having a decomposition endotherm withan onset in a range of about 190° C. to about 230° C. For example, insome embodiments oxalate crystalline salt form A is characterized byDSC, as shown in FIG. 48.

Oxalate crystalline salt form A also can be characterized bythermogravimetric analysis (TGA). Thus, oxalate crystalline salt form Acan be characterized by a weight loss in a range of about 0.5% to about4.5% with an onset temperature in a range of about 25° C. to about 100°C. For example, oxalate crystalline salt form A can be characterized bya weight loss of about 2.5%, up to about 150° C. In some embodiments,oxalate crystalline salt form A has a thermogravimetric analysissubstantially as depicted in FIG. 49, wherein by “substantially” ismeant that the reported TGA features can vary by about ±5° C.

Oxalate Crystalline Salt Form B

Oxalate crystalline salt form B of omecamtiv mecarbil can becharacterized by an X-ray powder diffraction pattern, obtained as setforth in the Examples, having peaks at about 7.38, 13.30, and 16.54±0.2°2θ using Cu Kα radiation. Oxalate crystalline salt form B optionally canbe further characterized by an X-ray powder diffraction pattern havingadditional peaks at about 17.11, 17.95, 18.45, 21.25, 22.63, 24.82, and25.77±0.2° 2θ using Cu Kα radiation. Oxalate crystalline salt form Boptionally can be further characterized by an X-ray powder diffractionpattern having additional peaks at about 14.76, 24.35, 28.61, 29.58,30.49, 31.76, 34.46, and 37.35±0.2° 2θ using Cu Kα radiation. Oxalatecrystalline salt form B can be characterized by an X-ray powderdiffraction pattern having peaks shown in Table 22 set forth in theExamples. In some embodiments, oxalate crystalline salt form B has anX-ray powder diffraction pattern substantially as shown in FIG. 50,wherein by “substantially” is meant that the reported peaks can vary byabout ±0.2°.

Oxalate crystalline salt form B also can be characterized bythermogravimetric analysis (TGA). Thus, oxalate crystalline salt form Bcan be characterized by a weight loss in a range of about 0% to about 1%with an onset temperature in a range of about 25° C. to about 100° C.For example, oxalate crystalline salt form B can be characterized by aweight loss of about 0%, up to about 150° C. In some embodiments,oxalate crystalline salt form B has a thermogravimetric analysissubstantially as depicted in FIG. 51, wherein by “substantially” ismeant that the reported TGA features can vary by about ±5° C.

Salicylate Crystalline Salt

The salicylate crystalline salt of omecamtiv mecarbil can becharacterized by an X-ray powder diffraction pattern, obtained as setforth in the Examples, having peaks at about 8.36, 16.75, 17.56, 23.58,and 28.21±0.2° 2θ using Cu Kα radiation. The salicylate crystalline saltoptionally can be further characterized by an X-ray powder diffractionpattern having additional peaks at about 10.08, 11.30, 13.69, 17.77,17.86, 18.67, 19.11, 20.22, 21.07, 25.23, and 27.40±0.2° 2θ using Cu Kαradiation. The salicylate crystalline salt optionally can be furthercharacterized by an X-ray powder diffraction pattern having additionalpeaks at about 9.78, 12.00, 13.80, 15.51, 19.27, 19.62, 20.02, 20.79,22.19, 22.39, 22.75, 22.92, 24.99, 25.59, 26.79, 29.94, and 34.07±0.2°2θ using Cu Kα radiation. The salicylate crystalline salt can becharacterized by an X-ray powder diffraction pattern having peaks shownin Table 24 set forth in the Examples. In some embodiments, thesalicylate crystalline salt has an X-ray powder diffraction patternsubstantially as shown in FIG. 53, wherein by “substantially” is meantthat the reported peaks can vary by about ±0.2°. In some embodiments,the salicylate crystalline salt has an TG/DTA substantially as shown inFIG. 54.

Hemi-Succinate Crystalline Salt

The hemi-succinate crystalline salt of omecamtiv mecarbil can becharacterized by an X-ray powder diffraction pattern, obtained as setforth in the Examples, having peaks at about 6.32, 18.87, 19.32, 20.5,21.24, 21.89, 23.49, 24.23, and 26.71±0.2° 2θ using Cu Kα radiation. Thehemi-succinate crystalline salt optionally can be further characterizedby an X-ray powder diffraction pattern having additional peaks at about12.93, 15.08, 16.97, 25.36, 27.39, and 28.32±0.2° 2θ using Cu Kαradiation. The hemi-succinate crystalline salt can be characterized byan X-ray powder diffraction pattern having peaks shown in Table 25 setforth in the Examples. In some embodiments, the hemi-succinatecrystalline salt has an X-ray powder diffraction pattern substantiallyas shown in FIG. 55, wherein by “substantially” is meant that thereported peaks can vary by about ±0.2°.

Differential scanning calorimetry (DSC) thermographs were obtained, asset forth in the Examples, for the hemi-succinate crystalline salt. TheDSC curve indicates an endothermic transition at about 171° C.±3° C.Thus, in some embodiments, the hemi-succinate crystalline salt can becharacterized by a DSC thermograph having a decomposition endotherm withan onset in a range of about 155° C. to about 190° C. For example, insome embodiments the hemi-succinate crystalline salt is characterized byDSC, as shown in FIG. 56.

Bis-Sulfate Crystalline Salt Form A

Bis-sulfate crystalline salt form A of omecamtiv mecarbil can becharacterized by an X-ray powder diffraction pattern, obtained as setforth in the Examples, having peaks at about 5.39, 7.55, 14.35, 19.26,and 20.22±0.2° 2θ using Cu Kα radiation. Bis-sulfate crystalline saltform A optionally can be further characterized by an X-ray powderdiffraction pattern having additional peaks at about 16.17, 16.71,16.92, 17.07, 18.60, 20.83, 21.38, 22.27, 22.77, 23.14, 23.42, 23.76,24.32, 25.11, 25.74, 26.46, 27.71, 28.15, and 29.92±0.2° 2θ using Cu Kαradiation. Bis-sulfate crystalline salt form A can be characterized byan X-ray powder diffraction pattern having peaks shown in Table 26 setforth in the Examples. In some embodiments, bis-sulfate crystalline saltform A has an X-ray powder diffraction pattern substantially as shown inFIG. 57, wherein by “substantially” is meant that the reported peaks canvary by about ±0.2°.

Bis-Sulfate Crystalline Salt Form B

Bis-sulfate crystalline salt form B of omecamtiv mecarbil can becharacterized by an X-ray powder diffraction pattern, obtained as setforth in the Examples, having peaks at about 11.72 and 20.48±0.2° 2θusing Cu Kα radiation. Bis-sulfate crystalline salt form B optionallycan be further characterized by an X-ray powder diffraction patternhaving additional peaks at about 12.17, 12.93, 17.79, 18.39, 18.76,19.84, 23.60, 25.13, 25.63, and 30.12±0.2° 2θ using Cu Kα radiation.Bis-sulfate crystalline salt form B can be characterized by an X-raypowder diffraction pattern having peaks shown in Table 27 set forth inthe Examples. In some embodiments, bis-sulfate crystalline salt form Bhas an X-ray powder diffraction pattern substantially as shown in FIG.58, wherein by “substantially” is meant that the reported peaks can varyby about ±0.2°.

Bis-sulfate crystalline salt form B also can be characterized bythermogravimetric analysis (TGA). Thus, bis-sulfate crystalline saltform B can be characterized by a weight loss in a range of about 10% toabout 14% with an onset temperature in a range of about 25° C. to about100° C. For example, bis-sulfate crystalline salt form B can becharacterized by a weight loss of about 12.2%, up to about 150° C. Insome embodiments, bis-sulfate crystalline salt form B has athermogravimetric analysis substantially as depicted in FIG. 59, whereinby “substantially” is meant that the reported TGA features can vary byabout ±5° C. This weight loss was determined to be water via KarlFischer (KF) analysis. KF analysis shows that the water content ofbis-sulfate crystalline salt form B can be about 12%, corresponding to apentahydrate.

Bis-Sulfate Crystalline Salt Form C

Bis-sulfate crystalline salt form C of omecamtiv mecarbil can becharacterized by an X-ray powder diffraction pattern, obtained as setforth in the Examples, having peaks at about 10.98, 11.49, 18.04, and19.60±0.2° 2θ using Cu Kα radiation. Bis-sulfate crystalline salt form Coptionally can be further characterized by an X-ray powder diffractionpattern having additional peaks at about 10.39, 10.72, 12.52, 12.99,17.11, 17.43, 20.94, 24.76, 25.25, 25.87, and 26.51±0.2° 2θ using Cu Kαradiation. Bis-sulfate crystalline salt form C can be characterized byan X-ray powder diffraction pattern having peaks shown in Table 28 setforth in the Examples. In some embodiments, bis-sulfate crystalline saltform C has an X-ray powder diffraction pattern substantially as shown inFIG. 60, wherein by “substantially” is meant that the reported peaks canvary by about ±0.2°.

Bis-sulfate crystalline salt form C also can be characterized bythermogravimetric analysis (TGA). Thus, bis-sulfate crystalline saltform C can be characterized by a weight loss in a range of about 7% toabout 11% with an onset temperature in a range of about 25° C. to about60° C. For example, bis-sulfate crystalline salt form C can becharacterized by a weight loss of about 9.0%, up to about 150° C. Insome embodiments, bis-sulfate crystalline salt form C has athermogravimetric analysis substantially as depicted in FIG. 61, whereinby “substantially” is meant that the reported TGA features can vary byabout ±5° C.

Sulfate Crystalline Salt Form D

Sulfate crystalline salt form D of omecamtiv mecarbil can becharacterized by an X-ray powder diffraction pattern, obtained as setforth in the Examples, having peaks at about 7.32, 8.02, and 20.44±0.2°2θ using Cu Kα radiation. Sulfate crystalline salt form D optionally canbe further characterized by an X-ray powder diffraction pattern havingadditional peaks at about 13.57, 14.54, 16.29, 16.41, 16.91, 17.36,18.70, 21.02, 21.77, 22.37, 22.90, 23.72, 24.28, 25.14, 25.88, 26.58,27.25, 28.10, and 29.43±0.2° 2θ using Cu Kα radiation. Sulfatecrystalline salt form D can be characterized by an X-ray powderdiffraction pattern having peaks shown in Table 29 set forth in theExamples. In some embodiments, sulfate crystalline salt form D has anX-ray powder diffraction pattern substantially as shown in FIG. 62,wherein by “substantially” is meant that the reported peaks can vary byabout ±0.2°. In embodiments, sulfate crystalline salt form D has aTG/DTA substantially as shown in FIG. 63.

2-Hydroxyethane Sulfonate Crystalline Salt

The 2-hydroxyethane sulfonate crystalline salt of omecamtiv mecarbil canbe characterized by an X-ray powder diffraction pattern, obtained as setforth in the Examples, having peaks at about 9.95, 17.85, 19.93, 20.07,20.46, 25.06, and 26.20±0.2° 2θ using Cu Kα radiation. The2-hydroxyethane sulfonate crystalline salt optionally can be furthercharacterized by an X-ray powder diffraction pattern having additionalpeaks at about 6.26, 6.69, 14.99, 16.37, 19.61, 20.95, 29.98, 32.16, and34.39±0.2° 2θ using Cu Kα radiation. The 2-hydroxyethane sulfonatecrystalline salt can be characterized by an X-ray powder diffractionpattern having peaks shown in Table 31 set forth in the Examples. Insome embodiments, the 2-hydroxyethane sulfonate crystalline salt has anX-ray powder diffraction pattern substantially as shown in FIG. 65,wherein by “substantially” is meant that the reported peaks can vary byabout ±0.2°. In some embodiments, the 2-hydroxyethane sulfonatecrystalline salt has a TG/DTA substantially as shown in FIG. 66.

Bis-Tartrate Crystalline Salt Form A

Bis-tartrate crystalline salt form A of omecamtiv mecarbil can becharacterized by an X-ray powder diffraction pattern, obtained as setforth in the Examples, having peaks at about 4.20, 7.49, 8.22, 11.88,16.42, and 21.19±0.2° 2θ using Cu Kα radiation. Bis-tartrate crystallinesalt form A optionally can be further characterized by an X-ray powderdiffraction pattern having additional peaks at about 4.77, 7.67, 8.43,9.49, 13.05, 13.26, 14.98, 15.14, 17.34, 17.47, 18.02, 18.23, 18.72,19.20, 22.50, 24.53, 25.67, 26.30, and 28.14±0.2° 2θ using Cu Kαradiation. Bis-tartrate crystalline salt form A can be characterized byan X-ray powder diffraction pattern having peaks shown in Table 32 setforth in the Examples. In some embodiments, bis-tartrate crystallinesalt form A has an X-ray powder diffraction pattern substantially asshown in FIG. 67, wherein by “substantially” is meant that the reportedpeaks can vary by about ±0.2°.

Bis-tartrate crystalline salt form A also can be characterized bythermogravimetric analysis (TGA). Thus, bis-tartrate crystalline saltform A can be characterized by a weight loss in a range of about 1% toabout 5% with an onset temperature in a range of about 25° C. to about120° C. For example, bis-tartrate crystalline salt form A can becharacterized by a weight loss of about 3.2%, up to about 150° C. Insome embodiments, bis-tartrate crystalline salt form A has athermogravimetric analysis substantially as depicted in FIG. 68, whereinby “substantially” is meant that the reported TGA features can vary byabout ±5° C.

Bis-Tartrate Crystalline Salt Form B

Bis-tartrate crystalline salt form B of omecamtiv mecarbil can becharacterized by an X-ray powder diffraction pattern, obtained as setforth in the Examples, having peaks at about 3.77, 5.69, and 10.07±0.2°2θ using Cu Kα radiation. Bis-tartrate crystalline salt form Boptionally can be further characterized by an X-ray powder diffractionpattern having additional peaks at about 4.72, 6.95, 9.34, 11.18, 12.63,15.18, 17.69, 22.35, and 25.46±0.2° 2θ using Cu Kα radiation.Bis-tartrate crystalline salt form B can be characterized by an X-raypowder diffraction pattern having peaks shown in Table 33 set forth inthe Examples. In some embodiments, bis-tartrate crystalline salt form Bhas an X-ray powder diffraction pattern substantially as shown in FIG.69, wherein by “substantially” is meant that the reported peaks can varyby about ±0.2°.

Bis-tartrate crystalline salt form B also can be characterized bythermogravimetric analysis (TGA). Thus, bis-tartrate crystalline saltform B can be characterized by a weight loss in a range of about 3% toabout 7% with an onset temperature in a range of about 20° C. to about100° C. For example, bis-tartrate crystalline salt form B can becharacterized by a weight loss of about 5.4%, up to about 150° C. Insome embodiments, bis-tartrate crystalline salt form B has athermogravimetric analysis substantially as depicted in FIG. 70, whereinby “substantially” is meant that the reported TGA features can vary byabout ±5° C.

Bis-Tartrate Crystalline Salt Form C

Bis-tartrate crystalline salt form C of omecamtiv mecarbil can becharacterized by an X-ray powder diffraction pattern, obtained as setforth in the Examples, having peaks at about 3.57, 6.23, and 15.84±0.2°2θ using Cu Kα radiation. Bis-tartrate crystalline salt form Coptionally can be further characterized by an X-ray powder diffractionpattern having additional peaks at about 3.86, 4.78, 7.04, 9.36, 13.08,13.96, 16.88, 17.60, 18.20, 18.73, 20.40, 22.58, 25.44, 26.06, and28.61±0.2° 2θ using Cu Kα radiation. Bis-tartrate crystalline salt formC can be characterized by an X-ray powder diffraction pattern havingpeaks shown in Table 34 set forth in the Examples. In some embodiments,bis-tartrate crystalline salt form C has an X-ray powder diffractionpattern substantially as shown in FIG. 71, wherein by “substantially” ismeant that the reported peaks can vary by about ±0.2°.

Bis-tartrate crystalline salt form C also can be characterized bythermogravimetric analysis (TGA). Thus, bis-tartrate crystalline saltform C can be characterized by a weight loss in a range of about 12% toabout 17% with an onset temperature in a range of about 20° C. to about100° C. For example, bis-tartrate crystalline salt form C can becharacterized by a weight loss of about 14.6%, up to about 150° C. Insome embodiments, bis-tartrate crystalline salt form C has athermogravimetric analysis substantially as depicted in FIG. 72, whereinby “substantially” is meant that the reported TGA features can vary byabout ±5° C.

Mono-Tartrate Crystalline Salt Form D

Mono-tartrate crystalline salt form D of omecamtiv mecarbil can becharacterized by an X-ray powder diffraction pattern, obtained as setforth in the Examples, having peaks at about 9.77 and 15.40±0.2° 2θusing Cu Kα radiation. Mono-tartrate crystalline salt form D optionallycan be further characterized by an X-ray powder diffraction patternhaving additional peaks at about 10.87, 13.79, 17.36, 17.74, 18.58,18.87, 21.78, 25.43, and 26.24±0.2° 2θ using Cu Kα radiation.Mono-tartrate crystalline salt form D can be characterized by an X-raypowder diffraction pattern having peaks shown in Table 35 set forth inthe Examples. In some embodiments, mono-tartrate crystalline salt form Dhas an X-ray powder diffraction pattern substantially as shown in FIG.73, wherein by “substantially” is meant that the reported peaks can varyby about ±0.2°.

Mono-tartrate crystalline salt form D also can be characterized bythermogravimetric analysis (TGA). Thus, mono-tartrate crystalline saltform D can be characterized by a weight loss in a range of about 4% toabout 8% with an onset temperature in a range of about 20° C. to about75° C. For example, mono-tartrate crystalline salt form D can becharacterized by a weight loss of about 6.4%, up to about 150° C. Insome embodiments, mono-tartrate crystalline salt form D has athermogravimetric analysis substantially as depicted in FIG. 74, whereinby “substantially” is meant that the reported TGA features can vary byabout ±5° C. This weight loss was determined to be water via KarlFischer (KF) analysis. KF analysis shows that the water content ofmono-tartrate crystalline salt form D can be about 6.9%, correspondingto a dihydrate.

Amorphous Hydrochloride Salt

Also provided herein is an amorphous hydrochloride salt of omecamtivmecarbil, and confirmation of its amorphous nature is provided by itsX-ray powder diffraction pattern as shown in FIG. 14.

Differential scanning calorimetry (DSC) thermographs were obtained, asset forth in the Examples, for the amorphous hydrochloride salt. The DSCcurve indicates an endothermic transition at about 171° C.±3° C. Thus,in some embodiments, the amorphous hydrochloride salt can becharacterized by a DSC thermograph having a decomposition endotherm withan onset in a range of about 155° C. to about 190° C. For example, insome embodiments the amorphous hydrochloride salt is characterized byDSC, as shown in FIG. 15.

The amorphous hydrochloride salt also can be characterized bythermogravimetric analysis (TGA). Thus, the amorphous hydrochloride saltcan be characterized by a weight loss in a range of about 6% to about10% with an onset temperature in a range of about 20° C. to about 60° C.For example, the amorphous hydrochloride salt can be characterized by aweight loss of about 7.9%, up to about 150° C. In some embodiments, theamorphous hydrochloride salt has a thermogravimetric analysissubstantially as depicted in FIG. 16, wherein by “substantially” ismeant that the reported TGA features can vary by about ±5° C. In someembodiments, the amorphous hydrochloride salt has a moisture sorptionprofile substantially as depicted in FIG. 17.

Pharmaceutical Compositions

Also provided herein are pharmaceutical compositions comprising a saltor crystalline form of omecamtiv mecarbil described herein; and apharmaceutically acceptable excipient.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose ligands, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio. The compositionsdescribed herein can be formulated for any form of administration. Invarious cases, the composition is for oral administration. In variouscases, the composition is in tablet form.

In some embodiments, the pharmaceutical compositions can include apharmaceutically acceptable carrier. The phrase “pharmaceuticallyacceptable carrier” as used herein means a pharmaceutically acceptablematerial, composition, or vehicle, such as a liquid or solid filler,diluent, excipient, solvent or encapsulating material. As used hereinthe language “pharmaceutically acceptable carrier” includes buffers,sterile water for injection, solvents, dispersion media, coatings,antibacterial and antifungal agents, isotonic and absorption delayingagents, and the like, compatible with pharmaceutical administration.Each carrier must be “acceptable” in the sense of being compatible withthe other ingredients of the formulation and not injurious to thepatient. Some examples of materials which can serve as pharmaceuticallyacceptable carriers include: (1) sugars, such as lactose, glucose, andsucrose; (2) starches, such as corn starch, potato starch, andsubstituted or unsubstituted β-cyclodextrin; (3) cellulose, and itsderivatives, such as sodium carboxymethyl cellulose, ethyl cellulose,and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin;(7) talc; (8) excipients, such as cocoa butter and suppository waxes;(9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil,olive oil, corn oil, and soybean oil; (10) glycols, such as propyleneglycol; (11) polyols, such as glycerin, sorbitol, mannitol, andpolyethylene glycol; (12) esters, such as ethyl oleate and ethyllaurate; (13) agar; (14) buffering agents, such as magnesium hydroxideand aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17)isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20)phosphate buffer solutions; and (21) other non-toxic compatiblesubstances employed in pharmaceutical formulations. In certainembodiments, pharmaceutical compositions provided herein arenon-pyrogenic, i.e., do not induce significant temperature elevationswhen administered to a patient.

Wetting agents, emulsifiers, and lubricants, such as sodium laurylsulfate and magnesium stearate, as well as coloring agents, releaseagents, coating agents, sweetening, flavoring, and perfuming agents,preservatives and antioxidants can also be present in the compositionsas excipients.

Examples of pharmaceutically acceptable antioxidants as excipientinclude: (1) water soluble antioxidants, such as ascorbic acid, cysteinehydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite,and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate,butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT),lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metalchelating agents, such as citric acid, ethylenediamine tetraacetic acid(EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

A pharmaceutical composition may also contain adjuvants such aspreservatives, wetting agents, emulsifying agents, and dispersingagents. Prevention of the action of microorganisms may be ensured by theinclusion of various antibacterial and antifungal agents, for example,paraben, chlorobutanol, phenol sorbic acid, and the like. It may also bedesirable to include tonicity-adjusting agents, such as sugars and thelike into the compositions. In addition, prolonged absorption of theinjectable pharmaceutical form may be brought about by the inclusion ofagents which delay absorption such as aluminum monostearate and gelatin.

In some cases, in order to prolong the effect of one or more compoundsprovided herein, it is desirable to slow the absorption of the compoundfrom subcutaneous or intramuscular injection. For example, delayedabsorption of a parenterally administered compound can be accomplishedby dissolving or suspending the compound in an oil vehicle.

The composition should be stable under the conditions of manufacture andstorage and must be preserved against the contaminating action ofmicroorganisms such as bacteria and fungi. Prevention of the action ofmicroorganisms can be achieved by various antibacterial and antifungalagents, for example, parabens, chlorobutanol, phenol, ascorbic acid,thimerosal, and the like. In many cases, it will be preferable toinclude isotonic agents, for example, sugars, polyalcohols such asmannitol, sorbitol, and sodium chloride in the composition. Prolongedabsorption of the injectable compositions can be brought about byincluding in the composition an agent that delays absorption, forexample, aluminum monostearate and gelatin.

Sterile injectable solutions can be prepared by incorporating the activecompound in the required amount in an appropriate solvent with one or acombination of ingredients enumerated above, as required, followed byfiltered sterilization. Generally, dispersions are prepared byincorporating the active compound into a sterile vehicle, which containsa basic dispersion medium and the required other ingredients from thoseenumerated above. In the case of sterile powders for the preparation ofsterile injectable solutions, the methods of preparation arefreeze-drying (lyophilization), which yields a powder of the activeingredient plus any additional desired ingredient from a previouslysterile-filtered solution thereof.

Injectable depot forms can be made by forming microencapsule ornanoencapsule matrices of a compound provided herein in biodegradablepolymers such as polylactide-polyglycolide. Depending on the ratio ofdrug to polymer, and the nature of the particular polymer employed, therate of drug release can be controlled. Examples of other biodegradablepolymers include poly(orthoesters) and poly(anhydrides). Depotinjectable formulations are also prepared by entrapping the drug inliposomes, microemulsions or nanoemulsions, which are compatible withbody tissue.

In one embodiment, the therapeutic crystalline salts are prepared withcarriers that will protect the therapeutic compounds against rapidelimination from the body, such as a controlled release formulation,including implants and microencapsulated delivery systems.Biodegradable, biocompatible polymers can be used, such as ethylenevinyl acetate, polyanhydrides, polyglycolic acid, collagen,polyorthoesters, and polylactic acid. Such formulations can be preparedusing standard techniques, or obtained commercially, e.g., from AlzaCorporation and Nova Pharmaceuticals, Inc. Liposomal suspensions(including liposomes targeted to selected cells with monoclonalantibodies to cellular antigens) can also be used as pharmaceuticallyacceptable carriers. These can be prepared according to methods known tothose skilled in the art, for example, as described in U.S. Pat. No.4,522,811, which is incorporated herein by reference in its entirety.

The pharmaceutical compositions can be included in a container, pack, ordispenser together with instructions for administration.

Controlled Release Compositions

In various cases, the pharmaceutical formulations described herein arecapable of releasing omecamtiv mecarbil evenly at a pace controlled bythe diffusion of omecamtiv mecarbil through a gel layer formed by thehydration of the control release agents in the tablets. In someembodiments, in conjunction with other above or below embodiments, thepresent modified release matrix tablets demonstrate a minimalpH-dependent release in-vitro. In some embodiments, in conjunction withother above or below embodiments, complete release of omecamtiv mecarbilis achieved in both pH 2 and 6.8 dissolution medium within 24 hours,possibly resulting in less inter- and intra-subject variability and foodeffect. It is found that the present modified release matrix tabletdosage form is superior to the former immediate release dosage form inminimizing the plasma peak-trough ratio. As a result, the presentmodified release matrix tablets reduce plasma concentration fluctuation,leading to reduced side effects, and improved safety and efficacy. It isalso expected that the present modified release matrix tablets willimprove patient compliance by reducing the dosing frequency.Additionally, the present modified release matrix tablets arephysicochemically stable—resulting in no physical attribute, assay,impurity, or dissolution profile changes after storage at 40° C./75% RHfor 6 months.

Provided are pharmaceutical formulations comprising the salt orcrystalline omecamtiv mecarbil as disclosed herein; a control releaseagent; a pH modifying agent; a filler; and a lubricant.

As used herein, the term “control release agents” refer to agents thatfacilitate the release of the active ingredient from the presentcomposition in a controlled fashion. In some embodiments, in conjunctionwith other above or below embodiments, the control release agents form agel upon hydration. Control release agents include pullulan, dextrin,sodium and calcium acid, polyacrylic acid, polymethacrylic acid,polymethylvinylether co-maleic anhydride, polyvinylpyrrolidone,polyethylene oxide, polyethylene glycol, hydroxypropylcellulose,hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxymethylmethacrylate, sodium carboxymethylcellulose, calciumcarboxymethylcellulose, methylcellulose, maltodextrin, xanthan gum,tragacanth gum, agar, gellan gum, kayara gum, alginic acids, pectins,pre-gelatinized starch, polyvinyl alcohol, carboxymethylethylcellulose,cellulose acetate phthalate, cellulose acetate succinate,methylcellulose phthate, hydroxymethylethylcellulosephthate,hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcelluloseacetate succinate, polyvinyl alcohol phthalate, polyvinyl butylatephthalate, polyvinyl actal phthalate, a copolymer of vinylacetate/maleic anhydride, a copolymer of styrene/maleic acid monoester,a copolymer of methyl acryl-ate/methacrylic acid, a copolymer ofstyrene/acrylic acid, a copolymer of methyl acrylate/methacrylicacid/octyl acrylate, a copolymer of methacrylic acid/methylmethacrylate, benzylaminomethylcellulose, diethylaminomethylcellulose,piperidylethylhydroxyethylcellulose, cellulose acetate dimethylaminoacetate, a copolymer of vinyl diethylamine/vinyl acetate, acopolymer of vinyl benzylamine/vinyl acetate, polyvinylacetaldiethylamino acetate, a copolymer ofvinylpiperidylacetoacetal/vinyl acetate, polydiethylaminomethylstyrene,a copolymer of methyl methacrylate/butyl methacrylate/dimethylaminoethylmethacrylate and polydimethylaminoethylmethacrylate, a copolymer of2-methyl-5-vinylpyridine/methylmethacrylate/methacrylic acid, acopolymer of 2-methyl-5-vinylpyridine/methyl acrylate/methacrylic acid,a copolymer of 2-vinyl-5-ethylpyridine/methacrylic acid/methy acrylate,a copolymer of 2-vinylpyrid-ine/methacrylic acid/acrylonitrile,carboxymethylpiperidyl starch, carboxy-methylbenzylaminocellulose, acopolymer of N-vinylglycine/styrene, chitosan, poly(vinyl alcohol),maleic anhydride copolymer, poly (vinyl pyrolidone), starch andstarch-based polymers, poly (2-ehtyl-2-oxazoline), poly(ethyleneimine),polyurethane hydrogels, welan gum, rhamsan gum, polyvinyl acetates,ethylcellulose, eudragit RL, RS, NE 30D, Kollicoat EMM 30D, orcombinations thereof.

In some embodiments, in conjunction with other above or belowembodiments, the control release agent is a polymer.

In some embodiments, in conjunction with other above or belowembodiments, the control release agent is selected from pullulan,dextrin, sodium and calcium acid, polyacrylic acid, polymethacrylicacid, polymethylvinylether co-maleic anhydride, polyvinylpyrrolidone,polyethylene oxide, polyethylene glycol, hydroxypropylcellulose,hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxymethylmethacrylate, sodium carboxymethylcellulose, calciumcarboxymethylcellulose, methylcellulose, maltodextrin, xanthan gum,tragacanth gum, agar, gellan gum, kayara gum, alginic acids, pectins,pre-gelatinized starch, polyvinyl alcohol, carboxymethylethylcellulose,cellulose acetate phthalate, cellulose acetate succinate,methylcellulose phthate, hydroxymethylethylcellulosephthate,hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcelluloseacetate succinate, polyvinyl alcohol phthalate, polyvinyl butylatephthalate, polyvinyl actal phthalate, a copolymer of vinylacetate/maleic anhydride, a copolymer of styrene/maleic acid monoester,a copolymer of methyl acryl-ate/methacrylic acid, a copolymer ofstyrene/acrylic acid, a copolymer of methyl acrylate/methacrylicacid/octyl acrylate, a copolymer of methacrylic acid/methylmethacrylate, benzylaminomethylcellulose, diethylaminomethylcellulose,piperidylethylhydroxyethylcellulose, cellulose acetatedimethylaminoacetate, a copolymer of vinyl diethylamine/vinyl acetate, acopolymer of vinyl benzylamine/vinyl acetate, polyvinylacetaldiethylamino acetate, a copolymer ofvinylpiperidylacetoacetal/vinyl acetate, polydiethylaminomethylstyrene,a copolymer of methyl methacrylate/butyl methacrylate/dimethylaminoethylmethacrylate and polydimethylaminoethyl methacrylate, a copolymer of2-methy-5vinylpyrid¬ine/methylmethacryl¬ate/methacrylic acid, acopolymer of 2-methyl-5-vinylpyridine/methyl acrylate/methacrylic acid,a copolymer of 2-vinyl-5-ethylpyridine/methacrylic acid/methy acrylate,a copolymer of 2-vinylpyrid-ine/methacrylic acid/acrylonitrile,carboxymethylpiperidyl starch, carboxy-methylbenzylaminocellulose, acopolymer of N-vinylglycine/styrene, chitosan, poly(vinyl alcohol),maleic anhydride copolymer, poly (vinyl pyrolidone), starch andstarch-based polymers, poly (2-ehtyl-2-oxazoline), poly(ethyleneimine),polyurethane hydrogels, welan gum, rhamsan gum, polyvinyl acetates,ethylcellulose, eudragit RL, RS, NE 30D, and Kollicoat EMM 30D, or anycombination thereof.

As used herein, the term “pH modifying agent” refers to an agent capableof modulating the pH to a desired range. In some embodiments, inconjunction with other above or below embodiments, the pH modifyingagent is an acidifying agent. In some embodiments, in conjunction withother above or below embodiments, the pH modifying agent is present inan amount sufficient to lower the pH. pH modifying agents include maleicacid, citric acid, tartaric acid, pamoic acid, fumaric acid, salicylicacid, 2,6-diaminohexanoic acid, camphorsulfonic acid, glycerophosphoricacid, 2-hydroxyethanesulfonic acid, isethionic acid, succinic acid,carbonic acid, p-toluenesulfonic acid, aspartic acid,8-chloro¬itheophylline, benezenesulfonic acid, malic acid, orotic acid,oxalic acid, benzoic acid, 2-naphthalenesulfonic acid, stearic acid,adipic acid, p-amino-isalicylic acid, 5-aminoslicylic acid, ascorbicacid, sulfuric acid, cyclamic acid, sodium lauryl sulfate, glucoheptonicacid, glucuronic acid, glycine, sulfuric acid, mandelic acid,1,5-naphthalenedisulfonic acid, nicotinic acid, oleic acid,2-oxoglutaric acid, pyridoxal 5-phosphate, undecanoic acid,p-acetamidobenzoic acid, o-acetamido-benzoic acid, m-acetamidobenzoicacid, N-acetyl-L-aspartic acid, camphoric acid, dehydrocholic acid,malonic acid, edetic acid, ethylenediainetetraacetic acid, ethylsulfuric acid, hydroxyphenylbenzoylbenzoic acid, glutamic acid, glycyrrhizicacid, 4-hexylresorcinol, hippuric acid, p-phenolsulfonic acid,4-hydroxybenzoic acid, 3-hydroxybenzoic acid, 3-hydroxy-2-naphthoicacid, 1-hydroxy-2naphthoic acid, lactobionic acid, 3′-adenylic acid,5′-adenylic acid, mucic acid, galactaric acid, pantothenic acid, pecticacid, polygalacturonic acid, 5-sulfosalicylic acid,1,2,3,6-tetrahydro-1,3-dimethyl-2,6-dioxopurine-7-propanesulfonic acid,terephthalic acid, 1-hydroxy-2naphthoic acid, and combinations thereof.In some embodiments, in conjunction with other above or belowembodiments, pH modifying agents include, for example, maleic acid,citric acid, malic acid, fumaric acid, sulfuric acid, tartaric acid,lactoic acid, salicylic acid, aspartic acid, aminosalicylic acid,malonic acid, glutamic acid, and combinations thereof. In someembodiments, in conjunction with other above or below embodiments, thepH modifying agent comprises fumaric acid, tartaric acid, glutamic acid,or a combination thereof.

In some embodiments, in conjunction with other above or belowembodiments, pH modifying agent includes maleic acid, citric acid,tartaric acid, pamoic acid, fumaric acid, salicylic acid,2,6-diaminohexanoic acid, camphorsulfonic acid, glycerophosphoric acid,2-hydroxyethanesulfonic acid, isethionic acid, succinic acid, carbonicacid, p-toluenesulfonic acid, aspartic acid, 8-chlorotheophylline,benezenesulfonic acid, malic acid, orotic acid, oxalic acid, benzoicacid, 2-naphthalenesulfonic acid, stearic acid, adipic acid,p-amino-salicylic acid, 5-aminoslicylic acid, ascorbic acid, sulfuricacid, cyclamic acid, sodium lauryl sulfate, glucoheptonic acid,glucuronic acid, glycine, sulfuric acid, mandelic acid,1,5-naphthalenedisulfonic acid, nicotinic acid, oleic acid,2-oxoglutaric acid, pyridoxal 5-phosphate, undecanoic acid,p-acetamidobenzoic acid, o-acetamidobenzoic acid, m-acetamidobenzoicacid, N-acetyl-L-aspartic acid, camphoric acid, dehydrocholic acid,malonic acid, edetic acid, ethylenediainetetraacetic acid, ethylsulfuric acid, hydroxyphenylbenzoylbenzoic acid, glutamic acid, glycyrrhizicacid, 4-hexylresorcinol, hippuric acid, p-phenolsulfonic acid,4-hydroxybenzoic acid, 3-hydroxybenzoic acid, 3-hydroxy-2-naphthoicacid, 1-hydroxy-2naphthoic acid, lactobionic acid, 3′-adenylic acid,5′-adenylic acid, mucic acid, galactaric acid, pantothenic acid, pecticacid, polygalacturonic acid, 5-sulfosalicylic acid,1,2,3,6-tetrahydro-1,3-dimethyl-2,6-dioxopurine-7-propanesulfonic acid,terephthalic acid, 1-hydroxy-2naphthoic acid, and combinations thereof.

In some embodiments, in conjunction with other above or belowembodiments, the pH modifying agent is selected from maleic acid, citricacid, malic acid, fumaric acid, sulfuric acid, tartaric acid, lactoicacid, salicylic acid, aspartic acid, aminosalicylic acid, malonic acid,glutamic acid, and any combination thereof.

In some embodiments, in conjunction with other above or belowembodiments, fumaric acid is used as the pH modifying agent as it isless hygroscopic and more compatible with omecamtiv mecarbildihydrochloride hydrate than citric acid, resulting in less or no activeform transformation and no changes in tablet appearance when stored atabout 40° C./75% RH for about 6 months, leading to improved finalproduct quality. Additionally, fumaric acid is more acidic (by about2-fold) than citric acid. Therefore, it is more efficient, i.e., about1:1 weight ratio to active instead of about 2:1, to use fumaric acid tomodulate the microenvironmental pH to enhance omecamtiv mecarbil releaseat neutral environment. Fumaric acid also has a very slow dissolutionrate. As a result, fumaric acid will stay in the tablet longer andmaintain the low micro-environmental pH better, resulting in morecomplete release of omecamtiv mecarbil within about 24 hours.

As used herein, the term “fillers” refers to one or more substances thatcan be added to components of a pharmaceutical composition to increasebulk weight of the material to be formulated, e.g. tabletted, in orderto achieve the desired weight. Fillers include but are not limited tostarches, lactose, mannitol (such as Pearlitol™ SD 200), cellulosederivatives, calcium phosphate, sugar and the like.

Different grades of lactose include, but are not limited, to lactosemonohydrate, lactose DT (direct tableting), lactose anhydrous, Flowlac™(available from Meggle products), Pharmatose™ (available from DMV) andothers. Different grades of starches include, but are not limited to,maize starch, potato starch, rice starch, wheat starch, pregelatinizedstarch (commercially available as PCS PC10 from Signet ChemicalCorporation) and Starch 1500, Starch 1500 LM grade (low moisture contentgrade) from Colorcon, fully pregelatinized starch (commerciallyavailable as National 78-1551 from Essex Grain Products) and others.Different cellulose compounds that can be used include crystallinecellulose and powdered cellulose. Examples of crystalline celluloseproducts include but are not limited to CEOLUS™ KG801, Avicel™ PH 101,PH102, PH301, PH302 and PH-F20, microcrystalline cellulose 114, andmicrocrystalline cellulose 112. Other useful fillers include, but arenot limited to, carmellose, sugar alcohols such as mannitol, sorbitoland xylitol, calcium carbonate, magnesium carbonate, dibasic calciumphosphate, and tribasic calcium phosphate.

In some embodiments, in conjunction with other above or belowembodiments, the filler is selected from starch, lactose, mannitol (suchas Pearlitol™ SD 200), cellulose derivatives, calcium phosphate, and asugar.

In some embodiments, in conjunction with other above or belowembodiments, the filler is lactose anhydrous or lactose monohydrate. Insome embodiments, in conjunction with other above or below embodiments,the filler is lactose DT, Flowlac™, or Pharmatose™′

In some embodiments, in conjunction with other above or belowembodiments, the filler is maize starch, potato starch, rice starch,wheat starch, pregelatinized starch (such as Starch 1500 or Starch 1500LM grade (low moisture content grade)), or fully pregelatinized starch.

In some embodiments, in conjunction with other above or belowembodiments, the filler is microcrystalline cellulose, such as CEOLUS™KG801, Avicel™ PH 101, PH102, PH301, PH302 and PH-F20, microcrystallinecellulose 114, or microcrystalline cellulose 112.

In some embodiments, in conjunction with other above or belowembodiments, the filler is carmellose, mannitol, sorbitol, xylitol,calcium carbonate, magnesium carbonate, dibasic calcium phosphate, ortribasic calcium phosphate.

As used herein, the term “lubricants” refers to one or more substancesthat can be added to components of the present compositions to reducesticking by a solid formulation to the equipment used for production ofa unit doss form. Lubricants include stearic acid, hydrogenatedvegetable oils, hydrogenated soybean oil and hydrogenated soybean oil &castor wax, stearyl alcohol, leucine, polyethylene glycol, magnesiumstearate, glycerylmonostearate, stearic acid, glycerybehenate,polyethylene glycol, ethylene oxide polymers, sodium lauryl sulfate,magnesium lauryl sulfate, sodium oleate, sodium stearyl fumarate,DL-leucine, colloidal silica, and mixtures thereof.

In some embodiments, in conjunction with other above or belowembodiments, the lubricant is stearic acid, hydrogenated vegetable oil,hydrogenated soybean oil, hydrogenated soybean oil, castor wax, stearylalcohol, leucine, polyethylene glycol, magnesium stearate,glycerylmonostearate, stearic acid, glycerybehenate, polyethyleneglycol, ethylene oxide polymers, sodium lauryl sulfate, magnesium laurylsulfate, sodium oleate, sodium stearyl fumarate, DL-leucine, colloidalsilica, or any mixture thereof.

Swellable Core Formulations

Provided herein are pharmaceutical formulations comprising: a drug layercomprising omecamtiv mecarbil as a salt or crystal form as disclosedherein; a sweller layer; and a semi-permeable membrane coating having atleast one delivery port.

Further provided are formulations comprising

a drug layer comprising:

-   -   omecamtiv mecarbil as a salt or crystal form as disclosed        herein;    -   a drug layer polymer; and    -   a lubricant;

a sweller layer comprising:

-   -   a sweller layer polymer;    -   an osmotic agent;    -   a diluent; and    -   a lubricant; and

a semi-permeable membrane coating having at least one delivery portcomprising:

-   -   an insoluble polymer; and    -   a pore forming polymer.

In some embodiments, in conjunction with other above or belowembodiments, the pharmaceutical formulation comprises:

a drug layer comprising: 10-20 (w/w %) omecamtiv mecarbil salt orcrystal form; 40-60 (w/w %) polyethylene oxide; and 0-2% (w/w %)lubricant;

a sweller layer comprising: 12-30 (w/w %) polyethylene oxide; 2-10 (w/w%) an osmotic agent; 1-8 (w/w %) microcrystalline cellulose; and 0.1-2(w/w %) lubricant; and

a semi-permeable membrane having at least one delivery port comprising:5-15 (w/w %) cellulose acetate; 0.3-5 (w/w %) polyethylene glycol.

In some embodiments, in conjunction with other above or belowembodiments, the pharmaceutical formulation comprises:

a drug layer comprising: 14-17 (w/w %) omecamtiv mecarbil salt orcrystal form; 48-55 (w/w %) polyethylene oxide; and 0.1-0.5% (w/w %)lubricant;

a sweller layer comprising: 18-25 (w/w %) polyethylene oxide; 4-9 (w/w%) an osmotic agent; 3-6 (w/w %) microcrystalline cellulose; and 0.1-0.5(w/w %) lubricant; and

a semi-permeable membrane having at least one delivery port comprising:8-10 (w/w %) cellulose acetate; 0.5-3 (w/w %) polyethylene glycol.

In some embodiments, in conjunction with other above or belowembodiments, the pharmaceutical formulation comprises:

a drug layer comprising: 10-20 (w/w %) omecamtiv mecarbil salt orcrystal form; 40-60 (w/w %) polyethylene oxide; and 0-2% (w/w %)magnesium stearate;

a sweller layer comprising: 12-30 (w/w %) polyethylene oxide; 2-10 (w/w%) sodium chloride; 1-8 (w/w %) microcrystalline cellulose; and 0.1-2(w/w %) magnesium stearate; and

a semi-permeable membrane having at least one delivery port comprising:5-15 (w/w %) cellulose acetate; 0.3-5 (w/w %) polyethylene glycol 3350.

In some embodiments, in conjunction with other above or belowembodiments, the pharmaceutical formulation comprises:

a drug layer comprising: 15-16 (w/w %) omecamtiv mecarbil salt orcrystal form; 50-52 (w/w %) PolyOx™ WSR N-80; and 0.1-0.5% (w/w %)magnesium stearate;

a sweller layer comprising: 20-23 (w/w %) PolyOx™ WSR Coagulant; 4-9(w/w %) sodium chloride; 3-6 (w/w %) Avicel PH 200; and 0.1-0.5 (w/w %)lubricant; and

a semi-permeable membrane having at least one delivery port comprising:8-10 (w/w %) cellulose acetate; 0.5-3 (w/w %) polyethylene glycol 3350.

In some embodiments, in conjunction with other above or belowembodiments, the pharmaceutical formulation comprises:

a drug layer comprising: 15-16 (w/w %) omecamtiv mecarbil salt orcrystal form; 50-52 (w/w %) PolyOx™ WSR N-80; and 0.1-0.5% (w/w %)magnesium stearate;

a sweller layer comprising: 20-23 (w/w %) PolyOx™ WSR Coagulant; 4-9(w/w %) sodium chloride; 3-6 (w/w %) Avicel PH 200; and 0.1-0.5 (w/w %)lubricant; and

a semi-permeable membrane having at least one delivery port comprising:8-9 (w/w %) cellulose acetate; 2-3 (w/w %) polyethylene glycol 3350.

In some embodiments, in conjunction with other above or belowembodiments, the pharmaceutical formulation comprises:

a drug layer comprising: 15-16 (w/w %) omecamtiv mecarbil salt orcrystal form; 50-52 (w/w %) PolyOx™ WSR N-80; and 0.1-0.5% (w/w %)magnesium stearate;

a sweller layer comprising: 20-23 (w/w %) PolyOx™ WSR Coagulant; 4-9(w/w %) sodium chloride; 3-6 (w/w %) Avicel PH 200; and 0.1-0.5 (w/w %)lubricant; and

a semi-permeable membrane having at least one delivery port comprising:9-10 (w/w %) cellulose acetate; 0.5-2 (w/w %) polyethylene glycol 3350.

Methods of Use

The omecamtiv mecarbil salt or crystal forms disclosed herein, or thepharmaceutical compositions described herein, may be used in thetreatment or prevention of heart failure, including but not limited to:acute (or decompensated) congestive heart failure, and chroniccongestive heart failure; particularly diseases associated with systolicheart dysfunction.

Also provided herein are methods of treating or preventing heart failurein a subject in need thereof comprising administering to the subject oneor more of the omecamtiv mecarbil salt or crystal forms disclosedherein, or one or more of the pharmaceutical compositions describedherein in an amount effective to treat or prevent heart failure. Furtherprovided are methods for the use of the disclosed salts and crystalforms of omecamtiv mecarbil, or compositions thereof, for the treatmentor prevention of heart failure, including but not limited to: acute (ordecompensated) congestive heart failure, and chronic congestive heartfailure; particularly diseases associated with systolic heartdysfunction.

Also provided herein is the use of the omecamtiv mecarbil salt orcrystal forms disclosed herein, or the pharmaceutical compositionsdescribed herein, in the manufacture of a medicament for the treatmentor prevention of heart failure. In some embodiments, the presentdisclosure provides use of the omecamtiv mecarbil salt or crystal formsdisclosed herein, or the pharmaceutical compositions described herein,in the manufacture of a medicament for the treatment of acute (ordecompensated) congestive heart failure, and chronic congestive heartfailure; particularly diseases associated with systolic heartdysfunction.

“Treatment” or “treating” includes one or more of: a) inhibiting adisease or disorder; b) slowing or arresting the development of clinicalsymptoms of a disease or disorder; and/or c) relieving a disease ordisorder, that is, causing the regression of clinical symptoms. The termcovers both complete and partial reduction of the condition or disorder,and complete or partial reduction of clinical symptoms of a disease ordisorder. Thus, the omecamtiv mecarbil salt or crystal forms describedherein, or the pharmaceutical compositions described herein may preventan existing disease or disorder from worsening, assist in the managementof the disease or disorder, or reduce or eliminate the disease ordisorder. “Prevention,” that is, causing the clinical symptoms of thedisease or disorder not to develop, includes the prophylacticadministration of a pharmaceutical formulation described herein to asubject (i.e., an animal, preferably a mammal, most preferably a human)believed to be in need of preventative treatment, such as, for example,chronic heart failure.

EXAMPLES

Methods

X-Ray Powder Diffraction

Procedure A: XRPD analysis was carried out on a PANalytical X'pert pro,scanning the samples between 3 and 35° 2θ. The material was gentlyground to release any agglomerates and loaded onto a multi-well platewith Kapton or Mylar polymer film to support the sample. The multi-wellplate was then placed into the diffractometer and analyzed using Cu Kradiation (α1λ=1.54060 Å; α2=1.54443 Å; β=1.39225 Å; α1:α2 ratio=0.5)running in transmission mode (step size 0.0130° 2θ) using 40 kV/40 mAgenerator settings.

Procedure B: XRPD analysis was carried out on a PANalytical X'pert pro,scanning the samples between 3 and 40° 2θ. The material was loaded ontoa zero background sample holder then placed into the diffractometer on aspinning stage at 1 rotation per second and analyzed using Cu Kradiation (α1λ=1.54060 Å; α2=1.54443 Å; β=1.39225 Å; α1:α2 ratio=0.5)running in transmission mode (step size 0.0167° 2θ) using 45 kV/40 mAgenerator settings.

Procedure C: X-Ray Powder Diffraction patterns were collected on aBruker AXS C2 GADDS diffractometer using Cu Kα radiation (40 kV, 40 mA),automated XYZ stage, laser video microscope for auto-sample positioningand a HiStar 2-dimensional area detector. X-ray optics consists of asingle GObel multilayer mirror coupled with a pinhole collimator of 0.3mm. The beam divergence, i.e. the effective size of the X-ray beam onthe sample, was approximately 4 mm. A θ-θ continuous scan mode wasemployed with a sample—detector distance of 20 cm which gives aneffective 2θ range of 3.2°-29.7°. Typically the sample would be exposedto the X-ray beam for 120 seconds. Ambient conditions. Samples run underambient conditions were prepared as flat plate specimens using powder asreceived with and without grinding. Approximately 1-2 mg of the samplewas lightly pressed on a glass slide to obtain a flat surface.

Differential Scanning Calorimetry (DSC)

Procedure A: Thermal properties were characterized using a DSC Q1000 orDSC Q100 model, TA Instruments, differential scanning calorimetry and aQ500, TA Instruments, thermogravimetric analyzer. Data analysis wasperformed utilizing Universal Analysis 2000, TA Instruments. Heatingrates of 1, 10 and 100° C./min were used over a variety of temperatureranges for differential scanning calorimetry and thermogravimetricanalysis. Samples ranging from 1-5 mg were prepared in crimped, hermeticor open aluminum pans for DSC analysis.

Procedure B: DSC data were collected on a TA Instruments Q2000 equippedwith a 50 position autosampler. The instrument was calibrated for energyand temperature calibration using certified indium. Typically 0.5-3 mgof each sample, in a pin-holed aluminum pan, was heated at 10° C./minfrom 25° C. to 350° C. A nitrogen purge at 50 ml/min was maintained overthe sample. The instrument control software was Thermal Advantage v4.6.6and the data were analyzed using Universal Analysis v4.3A.

Thermal Gravimetric/Differential Thermal Analysis (TG/DTA)

Approximately 5 mg of material was weighed into an open aluminum pan andloaded into a simultaneous thermogravimetric/differential thermalanalyzer (TG/DTA) and held at room temperature. The sample was thenheated at a rate of 10° C./min from 20° C. to 300° C. during which timethe change in sample weight was recorded along with any differentialthermal events (DTA). Nitrogen was used as the purge gas at a flow rateof 300 cm³/min.

Thermal Gravimetric Analysis

Procedure A: Thermograms were collected on a TA Instruments Q500thermogravimetric analyzer. Samples were loaded onto a platinum pan,1-10 mg, and heated at 10° C./min from ambient to 300° C.

Procedure B: TGA data were collected on a TA Instruments Q500 TGA,equipped with a 16 position auto-sampler. The instrument was temperaturecalibrated using certified Alumel. Typically 5-30 mg of each sample wasloaded onto a pre-tared platinum crucible and aluminum DSC pan, and washeated at 10° C./min from ambient temperature to 350° C. A nitrogenpurge at 60 ml/min was maintained over the sample. The instrumentcontrol software was Thermal Advantage v4.6.6 and the data were analyzedusing Universal Analysis v4.3A.

Moisture Sorption

Moisture balance was collected using a dynamic vapor sorption (DVS)analyzer. Relative humidity (RH) was set to 0, 5, 15, 25, 35, 45, 55,65, 75, 85 and 95% RH for 2 sorption/desorption cycles at 25° C.Equilibration criteria was set at 0.001% weight. Approximately 10 mg ofsample was used.

Solubility

An excess of solid was added to water, pH 1.0 or pH 4.5 buffer toproduce a suspension and dispersed for at least 24 at room temperature.Suspensions were filtered.

Filtrate was analyzed by HPLC-UV and compared against a standard curveto determine the solution concentration of the crystal form.

Experimental Section

Free base crystalline form Ill: Procedure A—prepared by adding 429 mg ofomecamtiv mecarbil to 20 mL of 2-propanol and 20 mL of water thenheating to 50° C. to dissolve then precipitate with 200 mL of water.

Procedure B—prepared during a solubility screen from 7 differentsolvents (2-BuOAc slurry, Cumene slurry, Isopropyl acetate slurry, MTBEslurry, heptane slurry, tBuOAc slurry or toluene slurry). 10 mg of freebase was placed in a vial and 50 μL aliquots for the first 300 μL, 100μL thereafter (up to 1 mL), of the solvents were added to the vial.Between each addition the mixture was checked for dissolution and if nodissolution was apparent the mixture was heated to ca. 50° C. andchecked again. This procedure was continued until dissolution wasobserved or until 100 volumes of solvent had been added. If nodissolution occurred the solid was filtered and an XRPD collected. Ifdissolution occurred, the cap was removed to allow evaporation of thesolvent and an XRPD of the remaining solid was collected. Free basecrystalline form III was then reproduced from a slurry in cumene,isopropyl acetate, MTBE or tBuOAc by adding 60 mg of lyophilized freebase to the solvent and gently heating to about 40° C.

The omecamtiv mecarbil free base crystalline form III was characterizedby an XRPD pattern comprising peaks in Table 1.

TABLE 1 Pos. FWHM d-spacing Height Rel. Int. [°2 Th.] [°2 Th.] [Å] [cts][%] 7.91 0.07 11.17 533.03 2.67 9.50 0.08 9.31 3776.76 18.91 14.27 0.106.21 15559.92 77.89 15.25 0.08 5.81 1095.46 5.48 16.10 0.10 5.51 1128.655.65 17.78 0.10 4.99 19975.52 100.00 19.06 0.10 4.66 2511.63 12.57 19.640.20 4.52 143.81 0.72 20.65 0.13 4.30 421.10 2.11 21.24 0.15 4.18 293.881.47 23.01 0.10 3.87 1285.85 6.44 23.87 0.10 3.73 1434.94 7.18 24.830.13 3.59 201.27 1.01 25.59 0.10 3.48 226.37 1.13 26.23 0.20 3.40 166.450.83 27.23 0.20 3.28 89.66 0.45 28.11 0.15 3.17 805.44 4.03 28.80 0.133.10 362.99 1.82 31.01 0.17 2.88 701.54 3.51 31.95 0.12 2.80 844.68 4.2332.34 0.20 2.77 605.43 3.03 33.67 0.13 2.66 248.53 1.24 34.69 0.13 2.59293.11 1.47 37.26 0.13 2.41 245.07 1.23 38.73 0.23 2.33 152.34 0.76

Free base crystalline form IV: was prepared by precipitation of 46 mg ofomecamtiv mecarbil from 2 mL THF with 2 mL n-butyl ether.

The omecamtiv mecarbil free base crystalline form IV was characterizedby an XRPD pattern comprising peaks in Table 2.

TABLE 2 Pos. FWHM d-spacing Height Rel. Int. [°2 Th.] [°2 Th.] [Å] [cts][%] 5.18 0.07 17.04 12067.81 100.00 7.42 0.10 11.91 322.11 2.67 7.700.08 11.48 416.99 3.46 10.35 0.07 8.55 814.51 6.75 10.81 0.10 8.19170.45 1.41 14.21 0.08 6.23 789.68 6.54 14.84 0.07 5.97 1276.45 10.5815.54 0.08 5.70 2686.48 22.26 17.10 0.10 5.18 122.93 1.02 18.10 0.104.90 10344.17 85.72 19.92 0.08 4.46 939.94 7.79 20.62 0.07 4.31 802.716.65 20.77 0.07 4.28 931.21 7.72 21.70 0.08 4.10 481.64 3.99 22.40 0.123.97 418.41 3.47 22.86 0.10 3.89 673.49 5.58 23.09 0.08 3.85 571.53 4.7424.05 0.08 3.70 774.58 6.42 24.36 0.12 3.65 752.02 6.23 25.20 0.10 3.53582.91 4.83 25.72 0.07 3.46 378.21 3.13 26.00 0.10 3.43 138.03 1.1426.68 0.27 3.34 93.44 0.77 27.40 0.10 3.26 400.49 3.32 27.81 0.12 3.21724.88 6.01 28.18 0.10 3.17 278.71 2.31 28.63 0.08 3.12 399.78 3.3128.98 0.08 3.08 480.22 3.98 29.42 0.10 3.04 644.30 5.34 30.51 0.13 2.93247.42 2.05 32.80 0.13 2.73 137.46 1.14 33.98 0.20 2.64 155.02 1.2835.34 0.20 2.54 147.52 1.22 36.38 0.20 2.47 110.92 0.92 37.12 0.20 2.42126.42 1.05

Free base crystalline form V: Procedure A—was prepared by adding 50 mgof omecamtiv mecarbil to 2 mL of THF at 60 C, filtering, then crashcooling by placing sample into an acetone/dry ice bath.

Procedure B—Free base crystalline form V was prepared during asolubility screen from 1,4-dioxane slurry. 10 mg of free base was placedin a Vial and 50 μL aliquots for the first 300 μL, 100 μL thereafter (upto 1 mL), of the solvent was added to the vial. Between each additionthe mixture was checked for dissolution and if no dissolution wasapparent the mixture was heated to ca. 50° C. and checked again. Thisprocedure was continued until dissolution was observed or until 100volumes of solvent had been added. If no dissolution occurred the solidwas filtered and an XRPD collected. If dissolution occurred, the cap wasremoved to allow evaporation of the solvent and an XRPD of the remainingsolid was collected.

The omecamtiv mecarbil free base crystalline form V was characterized byan XRPD pattern comprising peaks in Table 3.

TABLE 3 Pos. FWHM d-spacing Height Rel. Int. [°2 Th.] [°2 Th.] [Å] [cts][%] 5.40 0.10 16.37 213.79 7.88 7.38 0.07 11.98 470.25 17.33 8.56 0.0710.33 430.26 15.86 8.93 0.08 9.91 563.71 20.78 9.14 0.07 9.67 392.6614.47 10.03 0.08 8.82 375.08 13.82 10.73 0.13 8.25 332.70 12.26 11.710.12 7.56 840.50 30.98 13.69 0.17 6.47 335.68 12.37 15.08 0.18 5.88653.88 24.10 16.04 0.33 5.52 105.31 3.88 16.85 0.08 5.26 920.36 33.9217.85 0.13 4.97 2713.30 100.00 18.28 0.10 4.85 347.67 12.81 18.86 0.124.71 1897.24 69.92 20.05 0.20 4.43 1456.16 53.67 20.72 0.07 4.29 659.4924.31 21.74 0.17 4.09 354.74 13.07 22.83 0.27 3.90 189.17 6.97 23.560.10 3.78 1152.90 42.49 24.03 0.20 3.70 645.49 23.79 25.45 0.20 3.50217.43 8.01 26.23 0.10 3.40 366.63 13.51 27.62 0.23 3.23 654.84 24.1328.58 0.23 3.12 253.96 9.36 29.85 0.27 2.99 254.72 9.39 32.10 0.20 2.79233.50 8.61 33.37 0.33 2.69 165.44 6.10 35.47 0.27 2.53 105.15 3.8837.02 0.40 2.43 122.14 4.50

Free base crystalline form VI: was prepared by heating free basecrystalline form V to 150° C.

The omecamtiv mecarbil free base crystalline form VI was characterizedby an XRPD pattern comprising peaks in Table 4.

TABLE 4 Pos. FWHM d-spacing Height Rel. Int. [°2 Th.] [°2 Th.] [Å] [cts][%] 9.07 0.08 9.75 895.54 31.71 14.28 0.13 6.20 147.01 5.20 15.19 0.205.83 42.70 1.51 15.88 0.12 5.58 539.11 19.09 16.67 0.08 5.32 796.7428.21 17.81 0.08 4.98 1094.93 38.77 18.18 0.17 4.88 2824.51 100.00 18.800.12 4.72 850.75 30.12 19.70 0.10 4.51 1045.62 37.02 20.23 0.13 4.39185.58 6.57 20.89 0.10 4.25 1310.32 46.39 21.28 0.12 4.18 925.51 32.7723.72 0.08 3.75 691.60 24.49 24.26 0.08 3.67 784.97 27.79 26.19 0.203.40 146.84 5.20 26.80 0.17 3.33 235.58 8.34 27.59 0.13 3.23 347.6912.31 28.90 0.33 3.09 163.33 5.78 29.82 0.12 3.00 368.54 13.05

Free base crystalline form VII: was prepared during a solubility screenfrom water slurry. 10 mg of free base was placed in a vial and 50 μLaliquots for the first 300 μL, 1004 thereafter (up to 1 mL), of waterwas added to the vial. Between each addition the mixture was checked fordissolution and if no dissolution was apparent the mixture was heated toca. 50° C. and checked again. This procedure was continued untildissolution was observed or until 100 volumes of solvent had been added.The solid was filtered and an XRPD collected.

The omecamtiv mecarbil free base crystalline form VII was characterizedby an XRPD pattern comprising peaks in Table 5.

TABLE 5 Pos. FWHM d-spacing Height Rel. Int. [°2 Th.] [°2 Th.] [Å] [cts][%] 4.37 0.08 20.24 4137.34 100.00 7.84 0.13 11.27 89.35 2.16 8.40 0.0610.52 285.34 6.90 8.71 0.08 10.15 172.30 4.16 10.81 0.15 8.19 74.73 1.8113.08 0.08 6.77 387.47 9.37 15.66 0.08 5.66 481.77 11.64 16.83 0.10 5.271596.66 38.59 18.92 0.10 4.69 1248.28 30.17 19.61 0.09 4.53 1696.1841.00 20.32 0.05 4.37 584.96 14.14 20.49 0.10 4.33 961.99 23.25 21.610.08 4.11 319.30 7.72 22.26 0.10 3.99 1149.06 27.77 23.22 0.08 3.83265.13 6.41 23.46 0.10 3.79 299.05 7.23 24.21 0.13 3.68 1205.74 29.1425.41 0.05 3.51 1016.23 24.56 27.58 0.13 3.23 318.93 7.71 29.53 0.153.02 279.27 6.75 30.13 0.15 2.97 221.71 5.36 31.32 0.61 2.86 95.23 2.30

The XRPD peaks unique to each of the free base crystalline forms III-VIIdisclosed herein are shown in Table 6.

TABLE 6 Free Base Crystalline Form Peaks Unique to Each Form (KA1 °)Form III 9.50 19.06 23.01 Form IV 5.18 10.35 14.84 15.54 18.10 19.92Form V 7.38 8.56 9.14 18.28 Form VI 9.07 16.67 18.18 19.70 20.89 21.28Form VII 8.40 8.71 13.08 15.66 19.61

Amorphous hydrochloride salt: An amorphous bis-hydrochloride salt wasprepared by dissolving 0.505 g of bis-hydrochloride monohydrate saltForm A in 20 mL of water, flash frozen in liquid nitrogen andlyophilized. Chloride analysis gave a result of 14.6% Cl which is inagreement with a bis-hydrochloride. Thermal analysis indicatesapproximately a 7.9% weight loss during heating due to loss of water anda Tg around 149° C. Vapor sorption studies show that the amorphous formis hygroscopic and converts to the crystalline bis-hydrochloridemonohydrate Form A.

Ethane Sulfonate crystalline salt: was prepared in a primary saltscreen. A 2 mL aliquot of acetone was added to ˜40 mg of free base. 1.05equivalents of ethane sulfonate as a 1M solution in THF were added andthe sample was temperature cycled for 3-5 days.

The omecamtiv mecarbil ethane sulfonate crystalline salt wascharacterized by an XRPD pattern comprising peaks in Table 7.

TABLE 7 Pos. FWHM d-spacing Height Rel. Int. [°2 Th.] [°2 Th.] [Å] [cts][%] 8.61 0.10 10.27 1864.81 100.00 13.61 0.15 6.51 141.09 7.57 16.140.10 5.49 1152.97 61.83 16.76 0.13 5.29 825.27 44.26 16.97 0.08 5.22914.05 49.02 17.23 0.13 5.15 1148.35 61.58 18.35 0.15 4.84 579.44 31.0719.20 0.20 4.62 710.28 38.09 20.27 0.20 4.38 781.89 41.93 20.73 0.084.28 1275.35 68.39 20.96 0.10 4.24 1275.82 68.42 23.73 0.20 3.75 494.4826.52 25.24 0.15 3.53 262.30 14.07 25.95 0.15 3.43 442.47 23.73 26.300.10 3.39 512.57 27.49 27.09 0.20 3.29 204.40 10.96 29.01 0.41 3.0874.97 4.02

Bis-fumarate crystalline salt form A: was prepared by dissolving 1equivalent of free base (4.104 g) and 2.1 equivalents of fumaric acid(as 84 mL in a 95% EtOH/water solution) in 20 mL of 90% THF in waterthen distilling under house vacuum at 50° C. An additional 92 mL ofwater and mono-fumarate Form A seed were added to induce precipitation.

The omecamtiv mecarbil bis-fumarate crystalline salt form A wascharacterized by an XRPD pattern comprising peaks in Table 8.

TABLE 8 Pos. FWHM d-spacing Height Rel. Int. [°2 Th.] [°2 Th.] [Å] [cts][%] 5.64 0.18 15.67 1058.97 74.12 8.83 0.27 10.01 92.99 6.51 10.80 0.178.20 144.21 10.09 12.04 0.20 7.35 271.90 19.03 15.76 0.17 5.62 249.6617.47 16.40 0.10 5.41 417.23 29.20 16.80 0.13 5.28 1428.74 100.00 17.940.20 4.94 167.95 11.76 18.32 0.13 4.84 247.68 17.34 19.38 0.17 4.58130.62 9.14 19.87 0.13 4.47 159.85 11.19 20.61 0.27 4.31 198.11 13.8721.55 0.13 4.12 445.40 31.17 21.87 0.13 4.06 589.24 41.24 22.03 0.134.04 583.89 40.87 22.88 0.13 3.89 300.01 21.00 23.61 0.10 3.77 1008.7070.60 23.87 0.13 3.73 1042.62 72.97 25.07 0.27 3.55 109.91 7.69 26.010.18 3.43 795.76 55.70 27.20 0.27 3.28 900.61 63.04 27.86 0.23 3.20317.54 22.23 29.55 0.27 3.02 61.88 4.33 31.04 0.20 2.88 103.03 7.2132.73 0.27 2.74 145.12 10.16 35.00 0.20 2.56 80.10 5.61 36.01 0.27 2.4962.22 4.35 36.54 0.23 2.46 138.74 9.71

Bis-fumarate crystalline salt form B: was prepared during DVS cycle ofbis-fumarate Form A.

The omecamtiv mecarbil bis-fumarate crystalline salt form B wascharacterized by an XRPD pattern comprising peaks in Table 9.

TABLE 9 Pos. FWHM d-spacing Height Rel. Int. [°2 Th.] [°2 Th.] [Å] [cts][%] 5.68 0.20 15.57 557.86 53.41 6.11 0.15 14.47 941.86 90.18 9.69 0.079.13 213.36 20.43 11.43 0.17 7.74 195.35 18.70 12.92 0.10 6.85 428.1841.00 13.13 0.08 6.74 739.41 70.80 14.34 0.40 6.18 52.05 4.98 15.95 0.205.56 656.27 62.84 16.83 0.23 5.27 142.59 13.65 17.22 0.20 5.15 178.0917.05 18.08 0.20 4.91 494.57 47.35 19.05 0.20 4.66 135.39 12.96 19.520.33 4.55 99.22 9.50 20.81 0.20 4.27 362.18 34.68 22.47 0.15 3.96 547.4152.41 22.95 0.27 3.87 553.11 52.96 24.53 0.20 3.63 147.89 14.16 26.040.20 3.42 434.11 41.57 27.01 0.13 3.30 1044.39 100.00 28.43 0.13 3.14313.18 29.99 31.37 0.27 2.85 59.28 5.68 32.32 0.23 2.77 49.90 4.78 34.890.40 2.57 65.58 6.28 35.89 0.23 2.50 54.73 5.24 37.16 0.20 2.42 68.516.56

Bis-fumarate crystalline salt form C: was prepared from slurry ofbis-fumarate Forms A and B in 2 mL water at RT. Water solubility wasdetermined to be 13.7 mg/mL (pH 3.1).

The omecamtiv mecarbil bis-fumarate crystalline salt form C wascharacterized by an XRPD pattern comprising peaks in Table 10.

TABLE 10 Pos. FWHM d-spacing Height Rel. Int. [°2 Th.] [°2 Th.] [A][cts] [%] 5.88 0.17 15.03 5167.95 100.00 10.38 0.54 8.53 75.90 1.4710.70 0.10 8.27 162.04 3.14 11.56 0.12 7.65 325.84 6.30 12.74 0.10 6.951330.99 25.75 13.56 0.12 6.53 529.65 10.25 15.33 0.13 5.78 181.25 3.5116.85 0.10 5.26 336.53 6.51 17.15 0.12 5.17 1259.92 24.38 17.63 0.105.03 864.50 16.73 18.79 0.12 4.72 557.14 10.78 19.52 0.12 4.55 229.884.45 20.29 0.12 4.38 906.12 17.53 20.60 0.12 4.31 510.74 9.88 20.86 0.104.26 460.43 8.91 21.47 0.07 4.14 668.33 12.93 21.77 0.08 4.08 697.8713.50 22.21 0.13 4.00 865.69 16.75 22.92 0.13 3.88 864.48 16.73 23.580.13 3.77 792.02 15.33 24.15 0.07 3.68 600.60 11.62 24.55 0.13 3.63373.42 7.23 25.41 0.17 3.51 1064.69 20.60 26.37 0.12 3.38 254.11 4.9226.78 0.12 3.33 1601.63 30.99 26.86 0.06 3.33 1640.39 31.74 27.31 0.123.26 450.94 8.73 27.83 0.16 3.20 618.62 11.97 28.97 0.06 3.08 340.416.59 29.93 0.24 2.98 283.61 5.49 30.37 0.24 2.94 102.99 1.99 31.97 0.202.80 88.93 1.72 32.37 0.29 2.76 67.32 1.30 33.10 0.16 2.70 128.77 2.4934.02 0.33 2.63 173.14 3.35 35.76 0.29 2.51 160.08 3.10 38.14 0.24 2.3676.60 1.48 38.88 0.33 2.31 187.08 3.62 39.55 0.20 2.28 104.38 2.02

Mono-fumarate crystalline salt form D: was first prepared during a highthroughput screen by adding 0.3 mL of a 0.05M solution of free base inmethanol and 0.3 mL of a fumaric acid 0.05M solution in methanol to aglass plate then solvent was evaporated then 0.4 mL of solvent (water,0.001 M HCl aq, acetone, acetonitrile or hexanes) was added and heatedto 50° C. for 4 hours then evaporated.

The omecamtiv mecarbil mono-fumarate crystalline salt form D wascharacterized by an XRPD pattern comprising peaks in Table 11.

TABLE 11 Pos. FWHM d-spacing Height Rel. Int. [°2 Th.] [°2 Th.] [Å][cts] [%] 8.01 0.09 11.04 102.83 59.94 12.11 0.11 7.31 72.99 42.55 12.670.13 6.99 50.43 29.40 14.46 0.13 6.12 83.35 48.59 15.20 0.19 5.83 55.3832.28 16.01 0.19 5.54 50.34 29.34 16.57 0.11 5.35 76.69 44.71 17.04 0.145.20 32.05 18.69 17.63 0.16 5.03 37.88 22.08 18.48 0.16 4.80 16.35 9.5320.02 0.11 4.43 34.71 20.23 20.51 0.22 4.33 31.27 18.23 21.75 0.16 4.0937.60 21.92 22.86 0.19 3.89 18.19 10.60 24.25 0.13 3.67 171.54 100.0024.97 0.19 3.57 82.03 47.82 25.84 0.13 3.45 41.01 23.91 26.17 0.16 3.4174.19 43.25 27.10 0.13 3.29 37.05 21.60 27.97 0.19 3.19 21.24 12.3828.61 0.19 3.12 11.11 6.48 29.21 0.16 3.06 37.43 21.82 30.69 0.25 2.9110.74 6.26 34.70 0.50 2.59 7.97 4.64 37.41 0.19 2.40 11.12 6.48 38.480.38 2.34 6.46 3.77

The XRPD peaks unique to each of the fumarate crystalline salts formsA-D disclosed herein are shown in Table 12.

TABLE 12 Fumarate Form Peaks Unique to Each Form (°2Th.) Form A 5.6415.76 22.03 23.87 Form B 5.68 6.11 13.13 18.08 22.47 Form C 5.88 18.7925.41 26.86 Form D 8.01 15.20 20.02

Bis-Maleate crystalline salt form A: Procedure A: was first preparedduring a high throughput screen by adding 0.2 mL of a 0.124M solution offree base in methanol and 0.2 mL of a maleic acid 0.25M solution inmethanol to a glass plate then solvent was evaporated then 0.2 mL ofsolvent (water, 0.001 M HCl aq or acetone) was added and heated to 50°C. for 4 hours then evaporated. Salt was scaled up by adding 100 mg freebase to an 8 mL vial and 5 mL methanol and gently heating to dissolve.Maleic acid (2 mL of a 0.25M solution in acetone) was added at roomtemperature. Precipitate was isolated by filtration.

Procedure B—bis-maleate crystalline salt form A was prepared bydissolving 3.011 g of free base (1 eq) and 1.828 g of maleic acid(solution in 8 mL MeOH; 2.1 eq) in 45 mL methanol at 60° C. then cooledto precipitate. Water solubility was determined to be 3.8 mg/mL (pH3.7).

Procedure C—bis-maleate crystalline salt form A was also prepared in aprimary salt screen. A 2 mL aliquot of 2-propanol, THF, acetonitrile,isopropyl acetate or acetone was added to ˜40 mg of free base. 1.05equivalents of maleic acid as a 1M solution in THF were added and thesample was temperature cycled for 3-5 days.

The omecamtiv mecarbil bis-maleate crystalline salt form A wascharacterized by an XRPD pattern comprising peaks in Table 13.

TABLE 13 Pos. FWHM d-spacing Height Rel. Int. [°2 Th.] [°2 Th.] [Å][cts] [%] 3.32 0.82 26.60 267.10 3.31 4.99 0.05 17.71 482.89 5.98 6.600.08 13.38 216.56 2.68 6.95 0.41 12.72 56.27 0.70 7.25 0.08 12.19 198.552.46 9.17 0.15 9.64 73.48 0.91 9.97 0.08 8.87 7989.17 98.97 10.56 0.088.38 1761.58 21.82 12.96 0.09 6.83 311.81 3.86 13.25 0.09 6.68 1227.2415.20 14.54 0.12 6.09 356.32 4.41 14.83 0.08 5.98 743.84 9.21 15.31 0.105.79 8072.29 100.00 15.53 0.09 5.71 2487.57 30.82 16.04 0.10 5.526086.12 75.40 16.38 0.10 5.41 2253.00 27.91 17.10 0.08 5.19 675.31 8.3717.44 0.12 5.08 3071.51 38.05 17.70 0.13 5.01 2667.01 33.04 18.17 0.104.88 932.80 11.56 18.45 0.10 4.81 273.07 3.38 19.00 0.13 4.67 2099.1826.00 19.33 0.08 4.59 392.68 4.86 20.13 0.14 4.41 1667.83 20.66 21.470.12 4.14 2989.90 37.04 21.83 0.08 4.07 1329.81 16.47 22.02 0.06 4.04747.10 9.26 22.31 0.10 3.98 822.83 10.19 22.44 0.09 3.96 1010.70 12.5223.02 0.10 3.86 347.42 4.30 23.15 0.10 3.84 372.20 4.61 23.58 0.13 3.77194.06 2.40 24.38 0.06 3.65 1003.21 12.43 24.64 0.09 3.61 876.08 10.8525.66 0.15 3.47 924.66 11.45 26.66 0.13 3.34 1042.71 12.92 26.96 0.133.31 4976.38 61.65 27.83 0.13 3.21 845.81 10.48 28.10 0.10 3.18 293.573.64 28.55 0.15 3.13 766.92 9.50 29.31 0.08 3.05 151.67 1.88 30.17 0.202.96 186.07 2.31 30.76 0.23 2.91 458.79 5.68 31.67 0.13 2.83 362.78 4.4932.01 0.13 2.80 453.36 5.62 32.25 0.13 2.78 561.46 6.96 32.67 0.18 2.74427.72 5.30 33.11 0.20 2.71 342.20 4.24 33.65 0.13 2.66 375.70 4.6534.17 0.10 2.62 370.55 4.59 34.39 0.10 2.61 643.90 7.98 34.51 0.15 2.60639.10 7.92

Bis-malonate crystalline salt: was prepared by dissolving 200.7 mg offree base (1 eq) and 525 μL of malonic acid in methanol (2.1 eq) in 5 mLmethanol at 50° C. then 0.5 mL IPAc was added to precipitate then heatcycled twice 40° C./RT. Water solubility was determined to be greaterthan 62 mg/mL (pH 3.69).

The omecamtiv mecarbil bis-malonate crystalline salt was characterizedby an XRPD pattern comprising peaks in Table 14.

TABLE 14 Pos. FWHM d-spacing Height Rel. Int. [°2 Th.] [°2 Th.] [Å][cts] [%] 4.74 0.09 18.64 734.38 65.86 9.30 0.13 9.51 262.93 23.58 11.370.13 7.78 1115.14 100.00 13.73 0.13 6.45 154.92 13.89 14.25 0.11 6.22902.82 80.96 15.13 0.16 5.86 567.42 50.88 15.69 0.11 5.65 94.13 8.4416.45 0.13 5.39 438.97 39.36 16.83 0.13 5.27 165.27 14.82 18.08 0.134.91 552.17 49.52 18.29 0.11 4.85 855.08 76.68 18.88 0.16 4.70 287.1325.75 19.54 0.13 4.54 232.73 20.87 20.14 0.08 4.41 819.11 73.45 20.770.11 4.28 300.42 26.94 21.21 0.25 4.19 192.92 17.30 23.32 0.16 3.81218.40 19.58 23.87 0.13 3.73 766.34 68.72 24.67 0.13 3.61 193.04 17.3125.72 0.22 3.46 82.90 7.43 26.51 0.22 3.36 211.46 18.96 27.59 0.13 3.23520.24 46.65 27.78 0.08 3.21 805.51 72.23 28.01 0.20 3.19 630.55 56.5428.90 0.28 3.09 273.00 24.48 29.68 0.22 3.01 33.94 3.04 30.18 0.22 2.9651.90 4.65 33.70 0.22 2.66 96.86 8.69 34.19 0.19 2.62 54.63 4.90 35.520.22 2.53 39.53 3.54 36.82 0.19 2.44 42.45 3.81 37.62 0.63 2.39 36.763.30

Mesylate crystalline salt form A: was prepared by dissolving 200.7 mg offree base (1 eq) and 68.1 μL of methanesulfonic acid (2.1 eq) in 5 mLmethanol at 50° C., 2 mL IPAc and 5 mL acetone were added toprecipitate. Water solubility was determined to be greater than 72 mg/mL(pH 1.39).

The omecamtiv mecarbil mesylate crystalline salt form A wascharacterized by an XRPD pattern comprising peaks in Table 15.

TABLE 15 Pos. FWHM d-spacing Height Rel. Int. [°2 Th.] [°2 Th.] [Å][cts] [%] 4.02 0.38 21.96 492.38 100.00 4.87 0.25 18.15 472.41 95.947.79 0.19 11.35 87.26 17.72 11.61 0.25 7.62 110.78 22.50 15.21 0.25 5.82120.46 24.46 15.86 0.25 5.59 76.35 15.51 16.51 0.19 5.37 103.12 20.9417.57 0.28 5.05 160.72 32.64 18.42 0.31 4.82 126.44 25.68 19.26 038 4.61218.37 44.35 20.53 0.19 4.33 98.62 20.03 21.55 0.13 4.12 184.64 37.5023.17 0.50 3.84 115.61 23.48 24.39 0.28 3.65 207.28 42.10 25.51 0.163.49 126.17 25.63 26.38 0.25 3.38 65.52 13.31 27.63 0.25 3.23 83.4316.94 30.85 0.38 2.90 29.23 5.94

Bis-mesylate crystalline salt form B: was prepared in a primary saltscreen. A 2 mL aliquot of 2-propanol was added to ˜40 mg of free base.1.05 equivalents of methanesulfonic acid as a 1M solution in THF wereadded and the sample was temperature cycled for 3-5 days then tert-butylmethyl ether was added as an antisolvent. Solubility in pH 1 and 4.5buffers was determined to be greater than 23 mg/mL.

The omecamtiv mecarbil bis-mesylate crystalline salt form B wascharacterized by an XRPD pattern comprising peaks in Table 16.

TABLE 16 Pos. FWHM d-spacing Height Rel. Int. [°2 Th.] [°2 Th.] [Å][cts] [%] 8.30 0.08 10.65 4139.68 77.69 8.94 0.06 9.89 358.87 6.73 9.590.08 9.22 222.95 4.18 10.78 0.08 8.21 360.97 6.77 11.15 0.05 7.94 127.572.39 11.66 0.09 7.59 724.49 13.60 12.15 0.09 7.28 3000.51 56.31 14.370.12 6.17 521.87 9.79 14.93 0.10 5.93 402.24 7.55 15.36 0.08 5.77 258.874.86 15.57 0.08 5.69 436.88 8.20 16.18 0.10 5.48 560.02 10.51 16.64 0.085.33 1864.30 34.99 16.81 0.08 5.27 744.70 13.98 17.07 0.06 5.19 2428.7645.58 17.19 0.09 5.16 3783.32 71.00 17.41 0.10 5.09 2291.40 43.00 17.760.12 4.99 1630.15 30.59 19.24 0.09 4.61 757.57 14.22 19.82 0.10 4.481081.40 20.29 20.29 0.12 4.38 2158.58 40.51 20.66 0.14 4.30 1716.4932.21 21.62 0.13 4.11 1236.28 23.20 22.04 0.13 4.03 739.53 13.88 22.390.15 3.97 5328.66 100.00 23.54 0.18 3.78 176.98 3.32 23.95 0.06 3.72593.98 11.15 24.60 0.12 3.62 1334.05 25.04 25.02 0.13 3.56 2954.89 55.4525.59 0.17 3.48 1527.25 28.66 25.89 0.12 3.44 581.20 10.91 26.14 0.183.41 329.04 6.17 26.49 0.13 3.36 171.39 3.22 27.14 0.12 3.29 637.2311.96 27.35 0.08 3.26 1259.20 23.63 27.41 0.05 3.26 1229.76 23.08 27.890.19 3.20 181.37 3.40 28.86 0.09 3.09 126.53 2.37 29.45 0.16 3.03 536.8810.08 29.89 0.25 2.99 142.78 2.68 31.11 0.31 2.87 220.88 4.15 32.47 0.252.76 129.04 2.42 33.10 0.19 2.70 166.58 3.13 33.51 0.25 2.67 417.91 7.8434.56 0.16 2.59 235.62 4.42

The XRPD peaks unique to each of the mesylate crystalline salts forms Aand B disclosed herein are shown in Table 17.

TABLE 17 Mesylate Form Peaks Unique to Each Form (°2Th.) Form A 4.024.87 15.21 15.86 20.53 24.39 Form B 8.30 8.94  9.59 12.15 14.37 19.8220.29 22.04 25.02

Bis-naphthalate-2-sulfonate crystalline salt: was prepared. For theprimary (small scale) screen a 2 mL aliquot of 2-propanol, THF,acetonitrile, isopropyl acetate, acetone or toluene was added to 40 mgof free base, 1.05 equivalents of naphthalate-2-sulfonate sodium saltand 1.0 eq of 1M hydrochloric acid were added then temperature cycledfor 3-5 days. The salt was analyzed by XRPD. For the secondary screen(scale-up) 1.05 eq of naphthalene-2-sulfonate and 2M hydrochloric acidin THF were added to 700 mg of free base in 7 mL of 2-propanol thentemperature cycled (RT to 40 C) for 3 days, filtered, dried in vacuumoven at ambient temperature. The salt was analyzed by XRPD, IR, HPLC, 1HNMR, PLM, TG/DTA, DSC, DVS, VH-XRPD, stability studies, thermodynamicsolubility studies, disproportionation studies and hydration studies.Solubility in pH 1 and 4.5 buffers was determined to be greater than 10mg/mL.

The omecamtiv mecarbil bis-naphthalate-2-sulfonate crystalline salt wascharacterized by an XRPD pattern comprising peaks in Table 18.

TABLE 18 Pos. FWHM d-spacing Height Rel. Int. [°2 Th.] [°2 Th.] [Å][cts] [%] 4.49 0.06 19.70 5776.56 100.00 6.25 0.08 14.14 572.59 9.916.65 0.20 13.29 561.77 9.73 8.95 0.10 9.88 138.06 2.39 9.72 0.15 9.1054.78 0.95 13.44 0.08 6.59 367.63 6.36 14.39 0.10 6.16 341.11 5.91 14.920.12 5.94 904.43 15.66 15.51 0.20 5.71 276.65 4.79 16.28 0.08 5.44918.98 15.91 17.02 0.20 5.21 280.34 4.85 18.20 0.10 4.87 1575.43 27.2718.62 0.13 4.77 3005.63 52.03 18.90 0.12 4.69 792.38 13.72 19.53 0.154.54 806.67 13.96 20.82 0.26 4.27 664.39 11.50 21.38 0.06 4.16 1580.8427.37 21.52 0.13 4.13 1906.58 33.01 22.02 0.18 4.04 410.81 7.11 22.430.15 3.96 364.89 6.32 22.80 0.23 3.90 479.37 8.30 24.40 0.10 3.65 608.5910.54 25.16 0.09 3.54 424.12 7.34 26.11 0.10 3.41 2521.03 43.64 27.010.13 3.30 388.79 6.73 27.77 0.15 3.21 210.15 3.64 29.67 0.15 3.01 314.295.44 30.21 0.26 2.96 233.20 4.04 30.78 0.20 2.90 266.96 4.62 31.63 0.362.83 418.96 7.25 33.42 0.31 2.68 268.71 4.65 34.00 0.20 2.64 207.67 3.60

Mono-napadisylate crystalline salt: was prepared during a highthroughput screen by adding 0.2 mL of a 0.124M solution of free base inmethanol and 0.2 mL of a 1,5-naphthalene-disulfonic acid 0.25M solutionin methanol to a glass plate then solvent was evaporated then 0.2 mL ofsolvent (acetonitrile or 0.001M HCl aq) was added and heated to 50° C.for 4 hours then evaporated. Salt was scaled up by adding 100 mg freebase to an 8 mL Vial and 3 mL methanol and gently heating to dissolve.1,5-naphthalene-disulfonic acid (2 mL of a 0.25 M solution) was added atroom temperature. Solids were collected after evaporation andfiltration. Water solubility was determined to be 0.3 mg/mL (pH 2.35).

The omecamtiv mecarbil mono-napadisylate crystalline salt wascharacterized by an XRPD pattern comprising peaks in Table 19.

TABLE 19 Angle d value Intensity Rel. Int. 2-Theta° Angstrom Count(Height) [%] 6.671 13.251 82.2 6.4 7.052 12.535 171 13.2 10.837 8.1642360 27.9 12.266 7.2159 516 39.9 13.409 6.6034 442 34.2 14.572 6.0789 46035.6 15.144 5.8503 356 27.6 15.75 5.6266 753 58.3 16.466 5.3837 788 6117.831 4.9745 1292 100 18.824 4.7141 469 36.3 19.938 4.4533 955 73.921.828 4.0716 829 64.2 22.868 3.8888 605 46.9 23.487 3.7877 477 36.924.339 3.6571 307 23.8 25.263 3.5253 393 30.5

Nicotinate crystalline salt: was prepared in a primary salt screen. A 2mL aliquot of THF was added to ˜40 mg of free base. 1.05 equivalents ofnicotinic acid were added and the sample was temperature cycled for 3-5days then evaporated.

The omecamtiv mecarbil nicotinate crystalline salt was characterized byan XRPD pattern comprising peaks in Table 20.

TABLE 20 Pos, FWHM d-spacing Height Rel. Int. [°2 Th.] [°2 Th.] [Å][cts] [%] 3.69 0.05 23.96 4182.86 73.17 7.36 0.06 12.01 1796.70 31.438.55 0.08 10.34 3192.46 55.85 9.13 0.08 9.69 3381.54 59.16 10.01 0.088.84 1830.40 32.02 11.70 0.10 7.56 135.02 2.36 12.43 0.09 7.12 759.0013.28 13.83 0.08 6.40 329.03 5.76 14.74 0.10 6.01 648.74 11.35 15.040.15 5.89 392.48 6.87 15.50 0.12 5.72 2090.66 36.57 16.70 0.09 5.313962.66 69.32 16.84 0.09 5.27 5013.53 87.70 17.62 0.10 5.03 2110.9736.93 17.87 0.12 4.96 510.00 8.92 18.30 0.12 4.85 3434.06 60.07 18.580.13 4.78 1509.52 26.41 18.85 0.10 4.71 353.23 6.18 19.59 0.13 4.532097.05 36.69 19.99 0.15 4.44 5716.36 100.00 20.34 0.17 4.37 2282.9839.94 20.76 0.15 4.28 2868.05 50.17 21.32 0.15 4.17 2273.73 39.78 22.030.14 4.03 1235.06 21.61 22.91 0.13 3.88 1620.93 28.36 23.43 0.14 3.803577.00 62.57 23.87 0.12 3.73 895.16 15.66 24.83 0.20 3.58 3276.98 57.3324.92 0.05 3.58 2632.73 46.06 25.40 0.16 3.50 1715.21 30.01 25.95 0.233.43 2961.06 51.80 26.85 0.11 3.32 1483.29 25.95 26.94 0.09 3.31 1729.5430.26 27.32 0.14 3.26 2177.84 38.10 28.01 0.19 3.18 1526.39 26.70 28.940.09 3.08 887.28 15.52 29.34 0.22 3.04 154.50 2.70 29.93 0.19 2.98217.00 3.80 31.00 0.22 2.88 319.34 5.59 31.44 0.12 2.84 286.19 5.0131.78 0.16 2.81 214.18 3.75 32.10 0.22 2.79 385.58 6.75 32.59 0.19 2.75320.31 5.60 32.94 0.12 2.72 259.73 4.54 33.23 0.22 2.69 207.23 3.6334.14 0.28 2.62 300.22 5.25 34.65 0.22 2.59 283.29 4.96

Oxalate crystalline salt form A: Procedure A—was prepared a highthroughput screen by adding 0.3 mL of a 0.05M solution of free base inmethanol and 0.3 mL of a oxalic acid 0.05M solution in methanol to aglass plate then solvent was evaporated then 0.4 mL of solvent (water,0.001 M HCl aq, acetone, acetonitrile or hexanes) was added and heatedto 50° C. for 4 hours then evaporated.

Procedure B—was prepared by dissolving 47 mg of free base in ˜10 mL ofmethanol, then 145 μL of a 102 mg/mL solution of oxalic acid was addedand sample was placed in a N₂ box. Solids were then slurried inwater/ethanol at RT.

The omecamtiv mecarbil oxalate crystalline salt form A was characterizedby an XRPD pattern comprising peaks in Table 21.

TABLE 21 Pos. FWHM d-spacing Height Rel. Int. [°2Th.] [°2Th.] [A] [cts][%] 6.48 0.16 13.64 163.25 62.74 10.36 0.22 8.54 17.19 6.61 11.85 0.147.47 24.67 9.48 13.01 0.16 6.81 86.11 33.10 14.79 0.11 5.99 75.91 29.1715.35 0.13 5.77 45.24 17.39 17.11 0.14 5.18 260.20 100.00 18.24 0.504.86 7.90 3.04 19.23 0.13 4.62 28.45 10.94 19.91 0.31 4.46 40.62 15.6121.48 0.19 4.14 55.28 21.25 22.07 0.19 4.03 25.22 9.69 22.75 0.19 3.9142.95 16.50 23.82 0.08 3.74 258.28 99.26 24.88 0.38 3.58 9.55 3.67 25.700.16 3.47 30.99 11.91 28.55 0.44 3.13 31.95 12.28 29.86 0.19 2.99 16.816.46 30.71 0.19 2.91 31.18 11.98 33.32 0.19 2.69 16.02 6.16

Oxalate crystalline salt form B: was prepared during vapor sorptionanalysis of oxalate crystalline salt form A.

The omecamtiv mecarbil oxalate crystalline salt form B was characterizedby an XRPD pattern comprising peaks in Table 22.

TABLE 22 Pos. FWHM d-spacing Height Rel. Int. [°2Th.] [°2Th.] [Å] [cts][%] 7.38 0.11 11.97 219.37 77.59 13.30 0.14 6.66 127.50 45.10 14.76 0.196.00 21.36 7.55 16.54 0.13 5.36 64.20 22.71 17.11 0.13 5.18 245.68 86.9017.95 0.09 4.94 166.30 58.82 18.45 0.11 4.81 91.52 32.37 21.25 0.09 4.18106.18 37.56 22.63 0.13 3.93 114.73 40.58 24.35 0.19 3.66 25.92 9.1724.82 0.19 3.59 73.08 25.85 25.77 0.16 3.46 282.73 100.00 28.61 0.253.12 25.78 9.12 29.58 0.13 3.02 25.44 9.00 30.49 0.38 2.93 17.89 6.3331.76 0.25 2.82 24.02 8.50 34.46 0.50 2.60 17.34 6.13 36.26 0.63 2.488.50 3.00 37.35 0.19 2.41 14.20 5.02

The XRPD peaks unique to each of the oxalate crystalline salt forms Aand B disclosed herein are shown in Table 23.

TABLE 23 Oxalate Form Peaks Unique to Each Form ([°2Th.]) Form A 6.4813.01 23.82 Form B 7.38 13.30 16.54

Salicylate crystalline salt: was prepared in a primary salt screen. A 2mL aliquot of 2-propanol or toluene was added to ˜40 mg of free base.1.05 equivalents of salicylic acid as a 1M solution in THF were addedand the sample was temperature cycled for 3-5 days then the 2-propanolwas evaporated.

The omecamtiv mecarbil salicylate crystalline salt was characterized byan XRPD pattern comprising peaks in Table 24.

TABLE 24 Pos. FWHM d-spacing Height Rel. Int. [°2Th.] [°2Th.] [Å] [cts][%] 8.36 0.06 10.58 5425.26 100.00 9.78 0.06 9.05 634.48 11.69 10.080.06 8.78 1112.62 20.51 10.37 0.05 8.53 164.07 3.02 11.30 0.06 7.831739.85 32.07 11.82 0.05 7.48 271.53 5.00 12.00 0.05 7.38 412.51 7.6013.69 0.06 6.47 843.47 15.55 13.80 0.04 6.42 717.86 13.23 14.25 0.156.21 74.68 1.38 15.51 0.09 5.71 588.40 10.85 16.75 0.09 5.29 3941.5472.65 17.56 0.06 5.05 2277.70 41.98 17.77 0.05 4.99 1649.96 30.41 17.860.08 4.97 2140.62 39.46 18.67 0.09 4.75 1989.60 36.67 19.11 0.08 4.641216.29 22.42 19.27 0.06 4.61 812.90 14.98 19.62 0.08 4.52 795.44 14.6620.02 0.08 4.43 709.58 13.08 20.22 0.13 4.39 1916.47 35.33 20.79 0.084.27 721.20 13.29 21.07 0.13 4.22 1935.15 35.67 21.78 0.09 4.08 313.945.79 22.19 0.05 4.01 532.25 9.81 22.39 0.10 3.97 665.30 12.26 22.75 0.083.91 677.94 12.50 22.92 0.06 3.88 673.25 12.41 23.58 0.13 3.77 3464.5863.86 24.10 0.10 3.69 257.32 4.74 24.99 0.10 3.56 457.77 8.44 25.23 0.093.53 1162.00 21.42 25.59 0.09 3.48 506.81 9.34 26.79 0.09 3.33 620.9511.45 27.40 0.17 3.26 1709.43 31.51 27.78 0.15 3.21 231.91 4.27 28.210.18 3.16 2479.45 45.70 28.76 0.10 3.10 278.54 5.13 29.32 0.13 3.05236.55 4.36 29.65 0.15 3.01 309.68 5.71 29.94 0.06 2.98 491.39 9.0630.50 0.13 2.93 198.15 3.65 31.34 0.31 2.85 86.35 1.59 32.15 0.20 2.78138.16 2.55 32.74 0.10 2.74 175.34 3.23 34 07 0.06 2.63 656.95 12.11

Hemi-succinate crystalline salt: as prepared during a high throughputscreen by adding 0.3 mL of a 0.05M solution of free base in methanol and0.3 mL of a succinic acid 0.05M solution in methanol to a glass platethen solvent was evaporated then 0.4 mL of solvent (water, 0.001 M HClaq, acetone, acetonitrile or hexanes) was added and heated to 50° C. for4 hours then evaporated. Water solubility was determined to be 7.4 mg/mL(pH 4.7).

The omecamtiv mecarbil hemi-succinate crystalline salt was characterizedby an XRPD pattern comprising peaks in Table 25.

TABLE 25 Angle d value Intensity Rel. Int. 2-Theta° Angstrom Count(Height) [%] 5.488 16.102 191 11.5 6.319 13.988 504 30.5 7.596 11.638237 14.3 12.932 6.8459 437 26.4 14.092 6.2847 245 14.8 15.079 5.8756 36121.8 16.971 5.2244 307 18.6 18.768 4.728 1654 100 19.318 4.5947 107464.9 20.495 4.3334 1229 74.3 21.244 4.1822 790 47.8 21.889 4.0604 84951.4 23.492 3.7869 1651 99.8 24.228 3.6736 531 32.1 25.364 3.5116 48829.5 26.671 3.3424 749 45.3 27.389 3.2563 636 38.5 28.316 3.1518 63538.4

Bis-sulfate crystalline salt form A: Procedure A—prepared during a highthroughput screen by adding 0.2 mL of a 0.124M solution of free base inmethanol and 0.2 mL of a sulfuric acid 0.25M solution in methanol to aglass plate then solvent was evaporated then 0.2 mL of solvent (THF or0.001M HCl aq) was added and heated to 50° C. for 4 hours thenevaporated. Salt was scaled up by adding 100 mg free base to an 8 mLvial and 4 mL methanol and gently heating to dissolve. Sulphuric acid (2mL of a 0.25 M solution) was added at room temperature. Solids werecollected after evaporation to dryness.

Procedure B—prepared by dissolving 200.7 mg free base (1 eq) and 1.05 mLof 1M sulfuric acid (2.1 eq) in 5 mL methanol at 50° C. then cooled toprecipitate.

Procedure C—formed when Form D was exposed to 40 C/75% RH storageconditions for 3 days. Water solubility was determined to be 16 mg/mL(pH 1.5).

The omecamtiv mecarbil bis-sulfate crystalline salt form A wascharacterized by an XRPD pattern comprising peaks in Table 26.

TABLE 26 Pos. FWHM d-spacing Height Rel. Int. [°2Th.] [°2Th.] [Å] [cts][%] 5.39 0.05 16.40 803.64 14.66 7.55 0.06 11.71 915.17 16.70 8.33 0.0510.62 247.72 4.52 10.13 0.08 8.73 62.00 1.13 14.35 0.09 6.17 3211.6658.60 14.63 0.08 6.05 340.15 6.21 15.12 0.09 5.86 414.53 7.56 15.64 0.095.66 517.83 9.45 16.00 0.10 5.54 503.75 9.19 16.17 0.09 5.48 833.4215.21 16.39 0.08 5.41 379.73 6.93 16.71 0.08 5.31 565.39 10.32 16.920.06 5.24 1727.49 31.52 17.07 0.08 5.19 1764.97 32.20 17.68 0.09 5.02464.46 8.47 18.33 0.09 4.84 344.30 6.28 18.60 0.08 4.77 648.56 11.8319.26 0.12 4.61 5480.54 100.00 19.75 0.10 4.50 350.13 6.39 20.22 0.084.39 1216.75 22.20 20.83 0.10 4.26 1272.51 23.22 21.03 0.08 4.23 507.329.26 21.38 0.09 4.16 1278.02 23.32 22.27 0.12 3.99 1717.52 31.34 22.770.09 3.90 602.87 11.00 23.14 0.13 3.84 1861.14 33.96 23.42 0.08 3.80727.12 13.27 23.76 0.12 3.75 1376.36 25.11 24.32 0.12 3.66 1360.34 24.8225.11 0.13 3.55 1608.13 29.34 25.48 0.41 3.50 169.13 3.09 25.74 0.133.46 2483.24 45.31 26.30 0.08 3.39 445.14 8.12 26.46 0.06 3.37 589.3310.75 27.71 0.06 3.22 1509.03 27.53 28.15 0.08 3.17 1156.37 21.10 28.900.08 3.09 415.94 7.59 29.24 0.09 3.05 516.64 9.43 29.92 0.06 2.99 927.2416.92 30.38 0.13 2.94 210.94 3.85 30.65 0.08 2.92 266.96 4.87 31.57 0.132.83 212.99 3.89 32.14 0.09 2.79 339.08 6.19 33.10 0.18 2.71 172.88 3.1533.78 0.20 2.65 181.24 3.31 34.22 0.15 2.62 131.00 2.39

Bis-sulfate crystalline salt form B: was prepared by dissolving 150 mgfree base in 20 mL of acetone and adding 22 μL of 17.6M sulfuric acidthen sonicating. Isolated solids were slurried in water at RT. Watersolubility was determined to by 9 mg/mL (pH 3.5).

The omecamtiv mecarbil bis-sulfate crystalline salt form B wascharacterized by an XRPD pattern comprising peaks in Table 27.

TABLE 27 Pos. FWHM d-spacing Height Rel. Int. [°2Th.] [°2Th.] [Å] [cts][%] 10.67 0.19 8.29 12.89 6.12 11.72 0.19 7.55 160.31 76.09 12.17 0.197.27 80.11 38.02 12.93 0.13 6.85 43.21 20.51 14.57 0.22 6.08 17.85 8.4717.79 0.13 4.99 30.92 14.67 18.39 0.11 4.82 82.79 39.29 18.76 0.09 4.7332.73 15.54 19.84 0.22 4.47 101.51 48.18 20.48 0.11 4.34 124.27 58.9821.34 0.25 4.16 11.41 5.41 21.90 0.25 4.06 10.23 4.86 23.60 0.17 3.77210.68 100.00 24.23 0.13 3.67 35.79 16.99 25.13 0.16 3.54 44.10 20.9325.63 0.19 3.48 98.90 46.94 29.30 0.31 3.05 29.96 14.22 30.12 0.13 2.9747.50 22.55 30.98 0.19 2.89 15.83 7.51 31.48 0.19 2.84 18.11 8.60 31.940.19 2.80 13.68 6.49 36.02 0.25 2.49 10.23 4.86 36.85 0.50 2.44 7.643.63 38.16 0.25 2.36 11.73 5.57

Bis-sulfate crystalline salt form C: was prepared by heating bis-sulfateForm B on TGA.

The omecamtiv mecarbil bis-sulfate crystalline salt form C wascharacterized by an XRPD pattern comprising peaks in Table 28.

TABLE 28 Pos. FWHM d-spacing Height Rel. Int. [°2Th.] [°2Th.] [Å] [cts][%] 8.20 0.19 10.79 30.31 4.27 10.39 0.13 8.51 179.40 25.28 10.72 0.098.25 226.72 31.94 10.98 0.13 8.06 252.05 35.51 11.49 0.22 7.70 136.5719.24 12.17 0.19 7.27 132.34 18.65 12.52 0.16 7.07 159.11 22.42 12.990.22 6.82 238.57 33.61 13.56 0.22 6.53 122.29 17.23 15.98 0.25 5.5537.67 5.31 16.74 0.19 5.30 135.94 19.15 17.11 0.16 5.18 296.18 41.7317.43 0.22 5.09 332.88 46.90 18.04 0.31 4.92 107.59 15.16 19.60 0.144.53 249.29 35.12 20.94 0.22 4.24 215.86 30.41 21.53 0.22 4.13 109.9815.50 22.47 0.31 3.96 100.45 14.15 23.09 0.28 3.85 136.51 19.23 23.980.31 3.71 58.62 8.26 24.76 0.19 3.60 230.19 32.43 25.25 0.31 3.53 709.74100.00 25.87 0.16 3.44 263.23 37.09 26.51 0.19 3.36 179.86 25.34 27.630.76 3.23 91.65 12.91 29.33 0.50 3.04 30.11 4.24 32.14 0.38 2.79 44.366.25 33.91 0.38 2.64 17.82 2.51 35.27 0.38 2.55 15.44 2.18 39.25 0.252.30 22.20 3.13

Sulfate crystalline salt form D: was prepared in a primary salt screen.To prepare Form D a 2 mL aliquot of acetone was added to ˜40 mg of freebase. 1.05 equivalents of sulfuric acid as a 1M solution in THF wereadded and the sample was temperature cycled for 3-5 days.

The omecamtiv mecarbil sulfate crystalline salt form D was characterizedby an XRPD pattern comprising peaks in Table 29.

TABLE 29 Pos. FWHM d-spacing Height Rel. Int. [°2Th.] [°2Th.] [Å] [cts][%] 7.32 0.08 12.08 844.93 59.30 8.02 0.05 11.03 224.63 15.77 11.67 0.107.58 138.68 9.73 12.20 0.10 7.25 169.56 11.90 12.55 0.10 7.05 121.398.52 13.57 0.08 6.52 1067.44 74.92 14.54 0.10 6.09 805.82 56.56 16.290.08 5.44 758.59 53.24 16.41 0.08 5.40 705.84 49.54 16.91 0.15 5.24520.14 36.51 17.36 0.20 5.11 373.69 26.23 18.70 0.06 4.74 783.62 55.0020.44 0.15 4.34 1424.79 100.00 21.02 0.15 4.23 587.18 41.21 21.77 0.154.08 625.52 43.90 22.37 0.15 3.97 403.56 28.32 22.90 0.15 3.88 1136.8679.79 23.72 0.15 3.75 749.74 52.62 24.28 0.08 3.67 771.24 54.13 25.140.13 3.54 490.08 34.40 25.88 0.10 3.44 399.16 28.02 26.58 0.09 3.35808.90 56.77 27.25 0.15 3.27 783.97 55.02 28.10 0.15 3.18 200.02 14.0429.43 0.18 3.04 218.32 15.32 30.45 0.41 2.94 99.72 7.00 33.15 0.31 2.7089.81 6.30 33.88 0.15 2.65 121.18 8.51

The XRPD peaks unique to each of the sulfate crystalline salt forms A-Ddisclosed herein are shown in Table 30.

TABLE 30 Sulfate Form Peaks Unique to Each Form ([°2Th.]) Form A 5.397.55 14.35 19.26 20.22 Form B 11.72 20.48 Form C 10.98 11.49 18.04 19.60Form D 7.32 8.02 20.44

2-Hydroxyethane sulfonate crystalline salt: was prepared in a primarysalt screen. A 2 mL aliquot of THF, acetonitrile or isopropyl acetatewas added to ˜40 mg of free base. 1.05 equivalents of 2-hydroxyethanesulfonic acid as a solid and 1 equivalent of 1M hydrochloric acid wereadded and the sample was temperature cycled for 3-5 days.

The omecamtiv mecarbil 2-hydroxyethane sulfonate crystalline salt wascharacterized by an XRPD pattern comprising peaks in Table 31.

TABLE 31 Pos. FWHM d-spacing Height Rel. Int. [°2Th.] [°2Th.] [Å] [cts][%] 6.26 0.08 14.13 219.45 9.02 6.69 0.18 13.21 374.53 15.39 9.95 0.068.89 2434.20 100.00 14.43 0.15 6.14 98.15 4.03 14.99 0.23 5.91 360.3514.80 15.51 0.15 5.71 182.59 7.50 16.37 0.09 5.41 438.44 18.01 17.060.26 5.20 148.91 6.12 17.85 0.08 4.97 916.01 37.63 19.61 0.15 4.53272.20 11.18 19.93 0.05 4.46 695.74 28.58 20.07 0.06 4.42 590.93 24.2820.46 0.12 4.34 487.31 20.02 20.95 0.18 4.24 261.07 10.73 22.06 0.184.03 158.42 6.51 22.89 0.26 3.88 158.38 6.51 23.96 0.15 3.71 128.47 5.2824.41 0.13 3.65 155.88 6.40 25.06 0.15 3.55 488.47 20.07 26.20 0.18 3.40632.72 25.99 26.98 0.20 3.30 133.39 5.48 27.92 0.08 3.20 162.41 6.6728.43 0.15 3.14 116.74 4.80 29.98 0.04 2.98 438.04 18.00 32.16 0.04 2.78443.24 18.21 33.38 0.41 2.68 86.61 3.56 34.39 0.06 2.61 387.48 15.92

Bis-tartrate crystalline salt form A: was prepared by dissolving 200.7mg (1 eq) of free base and 525 μL (30.02 g in 100 mL methanol, 2.1 eq)in 20 mL methanol and heat cycle 40° C./RT twice. Water solubility wasdetermined to be >53 mg/mL (pH 3.28).

The omecamtiv mecarbil bis-tartrate crystalline salt form A wascharacterized by an XRPD pattern comprising peaks in Table 32.

TABLE 32 Pos. FWHM d-spacing Height Rel. Int. [°2Th.] [°2Th.] [Å] [cts][%] 4.20 0.19 21.02 968.44 59.18 4.77 0.19 18.52 1062.98 64.96 7.49 0.1611.80 715.72 43.74 7.67 0.09 11.52 629.63 38.48 8.22 0.19 10.75 793.4148.48 8.43 0.09 10.49 699.24 42.73 9.49 0.19 9.32 377.23 23.05 11.180.25 7.91 193.33 11.81 11.88 0.31 7.45 208.48 12.74 13.05 0.22 6.79590.85 36.11 13.26 0.13 6.68 608.71 37.20 14.98 0.11 5.92 1399.17 85.5015.14 0.22 5.85 1490.06 91.05 16.42 0.35 5.40 437.01 26.70 17.34 0.085.11 983.61 60.11 17.47 0.14 5.08 1247.90 76.26 18.02 0.19 4.92 1121.3668.52 18.23 0.16 4.87 911.65 55.71 18.72 0.13 4.74 441.84 27.00 19.200.16 4.62 370.82 22.66 21.19 0.11 4.19 1636.46 100.00 22.50 0.19 3.95667.89 40.81 23.86 0.16 3.73 212.59 12.99 24.53 0.41 3.63 339.28 20.7325.67 0.38 3.47 528.93 32.32 26.30 0.31 3.39 451.92 27.62 28.14 0.253.17 388.50 23.74 28.44 0.22 3.14 285.60 17.45 29.87 0.38 2.99 258.3315.79 31.32 0.31 2.86 101.08 6.18 32.48 0.25 2.76 128.85 7.87 33.69 0.252.66 103.91 6.35 34.42 0.25 2.61 158.44 9.68 35.36 0.31 2.54 97.83 5.9835.92 0.19 2.50 84.54 5.17 36.60 0.31 2.46 82.62 5.05 37.41 0.25 2.40136.23 8.32 37.88 0.25 2.38 96.44 5.89

Bis-tartrate crystalline salt form B: was prepared by dissolving 1.004 gof omecamtiv mecarbil and 0.788 g L-tartaric acid (2.1 eq) in 50 mL ofMeOH at 50° C. then cooling to precipitate.

The omecamtiv mecarbil bis-tartrate crystalline salt form B wascharacterized by an XRPD pattern comprising peaks in Table 33.

TABLE 33 Pos. FWHM d-spacing Height Rel. Int. [°2Th.] [°2Th.] [Å] [cts][%] 3.77 0.17 23.43 971.26 100.00 4.72 0.27 18.74 635.71 65.45 5.69 0.2715.52 516.33 53.16 6.95 0.27 12.73 358.34 36.89 9.34 0.27 9.46 200.3520.63 10.07 0.23 8.78 434.70 44.76 11.18 0.54 7.92 167.11 17.21 12.630.20 7.01 158.00 16.27 15.18 0.20 5.84 190.67 19.63 17.69 0.17 5.01282.08 29.04 22.35 0.20 3.98 177.49 18.27 25.46 0.40 3.50 62.01 6.38

Bis-tartrate crystalline salt form C: was prepared by slurry ofbis-tartrate Form B in water.

The omecamtiv mecarbil bis-tartrate crystalline salt form C wascharacterized by an XRPD pattern comprising peaks in Table 34.

TABLE 34 Pos. FWHM d-spacing Height Rel. Int. [°2Th.] [°2Th.] [A] [cts][%] 3.57 0.13 24.73 920.53 89.99 3.86 0.15 22.88 1022.92 100.00 4.780.40 18.49 513.98 50.25 6.23 0.20 14.19 427.74 41.82 7.04 0.13 12.56270.90 26.48 9.36 0.17 9.45 637.85 62.36 13.08 0.10 6.77 549.91 53.7613.96 0.17 6.34 239.78 23.44 15.84 0.17 5.59 348.37 34.06 16.88 0.205.25 121.74 11.90 17.60 0.27 5.04 146.72 14.34 18.20 0.20 4.87 147.0614.38 18.73 0.23 4.74 245.18 23.97 20.40 0.20 4.35 268.32 26.23 22.580.27 3.94 120.04 11.73 25.44 0.40 3.50 192.03 18.77 26.06 0.47 3.42213.11 20.83 28.61 0.40 3.12 106.58 10.42

Mono-tartrate crystalline salt form D: was prepared by mixing 1.004 g ofomecamtiv mecarbil and 0.375 g of L-tartaric acid (1 eq) in 10 mL of 5%H₂O in THF at 50° C. then cooling to precipitate.

The omecamtiv mecarbil mono-tartrate crystalline salt form D wascharacterized by an XRPD pattern comprising peaks in Table 35.

TABLE 35 Pos. FWHM d-spacing Height Rel. Int. [°2Th.] [°2Th.] [Å] [cts][%] 6.94 0.12 12.74 377.02 15.46 9.77 0.17 9.05 478.47 19.62 10.87 0.178.14 2097.98 86.02 12.74 0.13 6.95 204.81 8.40 13.04 0.13 6.79 144.175.91 13.79 0.15 6.42 871.83 35.75 14.54 0.20 6.09 418.22 17.15 14.860.13 5.96 315.83 12.95 15.40 0.18 5.75 2345.40 96.17 17.36 0.18 5.111127.77 46.24 17.74 0.17 5.00 512.38 21.01 18.58 0.12 4.78 598.49 24.5418.87 0.17 4.70 693.22 28.42 19.25 0.17 4.61 322.02 13.20 20.71 0.134.29 293.45 12.03 21.78 0.17 4.08 1734.64 71.13 23.11 0.20 3.85 97.514.00 23.58 0.13 3.77 214.55 8.80 24.69 0.12 3.61 423.81 17.38 25.43 0.173.50 2438.82 100.00 26.24 0.20 3.40 529.42 21.71 26.50 0.13 3.36 437.7517.95 26.99 0.27 3.30 259.96 10.66 28.58 0.27 3.12 73.70 3.02 29.43 0.273.03 100.12 4.11 30.40 0.13 2.94 161.38 6.62 32.74 0.27 2.74 127.69 5.2434.76 0.17 2.58 210.18 8.62 35.46 0.17 2.53 118.22 4.85 36.31 0.20 2.47191.26 7.84 37.01 0.13 2.43 138.71 5.69 37.64 0.27 2.39 131.07 5.37

The XRPD peaks unique to each of the tartrate crystalline salt forms A-Ddisclosed herein are shown in Table 36.

TABLE 36 Tartrate Form Peaks Unique to Each Form (°2Th.) Form A 4.20 7.49  8.22 11.88 16.42 21.19 Form B 3.77  5.69 10.07 Form C 3.57  6.2315.84 Form D 9.77 15.40

What is claimed:
 1. An omecamtiv mecarbil free base crystalline formwhich is any one of the following forms: i) an omecamtiv mecarbil freebase crystalline form III, characterized by an X-ray powder diffraction(XRPD) pattern comprising peaks at 9.50, 19.06, and 23.01±0.2° 2θ usingCu Kα radiation; ii) an omecamtiv mecarbil free base crystalline formIV, characterized by an X-ray powder diffraction (XRPD) patterncomprising peaks at 5.18, 10.35, 14.84, 15.54, 18.10, and 19.92±0.2° 2θusing Cu Kα radiation; iii) an omecamtiv mecarbil free base crystallineform V, characterized by an X-ray powder diffraction (XRPD) patterncomprising peaks at 7.38, 8.56, 9.14, and 18.28±0.2° 2θ using Cu Kαradiation; iv) an omecamtiv mecarbil free base crystalline form VI,characterized by an X-ray powder diffraction (XRPD) pattern comprisingpeaks at 9.07, 16.67, 18.18, 19.70, 20.89, and 21.28±0.2° 2θ using Cu Kαradiation; or v) an omecamtiv mecarbil free base crystalline form VII,characterized by an X-ray powder diffraction (XRPD) pattern comprisingpeaks at 8.40, 8.71, 13.08, 15.66, and 19.61±0.2° 2θ using Cu Kαradiation.
 2. The omecamtiv mecarbil free base crystalline form of claim1, wherein the crystalline form is omecamtiv mecarbil free basecrystalline form III, characterized by an X-ray powder diffraction(XRPD) pattern comprising peaks at 9.50, 19.06, and 23.01±0.2° 2θ usingCu Kα radiation.
 3. The omecamtiv mecarbil free base crystalline formIII of claim 2, further characterized by XRPD pattern peaks at 14.27,15.25, 16.10, 17.78, and 23.87±0.2° 2θ using Cu Kα radiation.
 4. Theomecamtiv mecarbil free base crystalline form III of claim 2, furthercharacterized by XRPD pattern peaks at 7.91, 20.65, 28.11, 31.01, 31.95,and 32.34±0.2° 2θ using Cu Kα radiation.
 5. The omecamtiv mecarbil freebase crystalline form III of claim 2, having an XRPD patternsubstantially as shown in FIG.
 1. 6. The omecamtiv mecarbil free basecrystalline form III of claim 2, having an endothermic transition at175° C. to 190° C., as measured by differential scanning calorimetry. 7.The omecamtiv mecarbil free base crystalline form III of claim 6,wherein the endothermic transition is at 186° C.±3° C.
 8. The omecamtivmecarbil free base crystalline form III of claim 2, having athermogravimetric analysis (TGA) substantially as shown in FIG.
 3. 9.The omecamtiv mecarbil free base crystalline form of claim 5, whereinthe crystalline form is omecamtiv mecarbil free base crystalline formIV, characterized by an X-ray powder diffraction (XRPD) patterncomprising peaks at 5.18, 10.35, 14.84, 15.54, 18.10, and 19.92±0.2° 2θusing Cu Kα radiation.
 10. The omecamtiv mecarbil free base crystallineform IV of claim 9, further characterized by XRPD pattern peaks at14.21, 20.62, 20.77, 22.86, 24.05, 24.36, 27.81, and 29.42±0.2° 2θ usingCu Kα radiation.
 11. The omecamtiv mecarbil free base crystalline formIV of claim 9, further characterized by XRPD pattern peaks at 7.42,7.70, 21.70, 22.40, 23.09, 25.20, 25.72, 27.40, 28.18, 28.63, 28.98, and30.51±0.2° 2θ using Cu Kα radiation.
 12. The omecamtiv mecarbil freebase crystalline form IV of claim 9, having an XRPD patternsubstantially as shown in FIG.
 4. 13. The omecamtiv mecarbil free basecrystalline form IV of claim 9, having an endothermic transition at 175°C. to about 190° C., as measured by differential scanning calorimetry.14. The omecamtiv mecarbil free base crystalline form IV of claim 13,wherein the endothermic transition is at 185° C.±3° C.
 15. The omecamtivmecarbil free base crystalline form IV of claim 9, having athermogravimetric analysis (TGA) as shown in FIG.
 6. 16. The omecamtivmecarbil free base crystalline form of claim 1, wherein the crystallineform is omecamtiv mecarbil free base crystalline form V, characterizedby an X-ray powder diffraction (XRPD) pattern comprising peaks at 7.38,8.56, 9.14, and 18.28±0.2° 2θ using Cu Kα radiation.
 17. The omecamtivmecarbil free base crystalline form V of claim 16, further characterizedby XRPD pattern peaks at 8.93, 10.03, 10.73, 11.71, 13.69, 15.08, 16.85,17.85, 18.86, 20.05, 20.72, 21.74, 23.56, 24.03, 26.23, and 27.62±0.2°2θ using Cu Kα radiation.
 18. The omecamtiv mecarbil free basecrystalline form V of claim 16, further characterized by XRPD patternpeaks at 5.40, 16.04, 22.83, 25.45, 26.23, 27.62, 28.58, 29.85, 32.10,and 33.37±0.2° 2θ using Cu Kα radiation.
 19. The omecamtiv mecarbil freebase crystalline form V of claim 16, having an XRPD patternsubstantially as shown in FIG.
 7. 20. The omecamtiv mecarbil free basecrystalline form V of claim 16, having an endothermic transition at 175°C. to 190° C., as measured by differential scanning calorimetry.
 21. Theomecamtiv mecarbil free base crystalline form V of claim 20, wherein theendothermic transition is at 185° C.±3° C.
 22. The omecamtiv mecarbilfree base crystalline form V of claim 16, having a thermogravimetricanalysis (TGA) as shown in FIG.
 9. 23. The omecamtiv mecarbil free basecrystalline form of claim 1, wherein the crystalline form is omecamtivmecarbil free base crystalline form VI, characterized by an X-ray powderdiffraction (XRPD) pattern comprising peaks at 9.07, 16.67, 18.18,19.70, 20.89, and 21.28±0.2° 2θ using Cu Kα radiation.
 24. The omecamtivmecarbil free base crystalline form VI of claim 23, furthercharacterized by XRPD pattern peaks at 15.88, 17.81, 18.80, 23.72,24.26, 26.80, 27.59, and 29.82±0.2° 2θ using Cu Kα radiation.
 25. Theomecamtiv mecarbil free base crystalline form VI of claim 23, furthercharacterized by XRPD pattern peaks at 14.28, 20.23, 26.19, and28.90±0.2° 2θ using Cu Kα radiation.
 26. The omecamtiv mecarbil freebase crystalline form VI of claim 23, having an XRPD patternsubstantially as shown in FIG.
 10. 27. The omecamtiv mecarbil free basecrystalline form VI of claim 23, having an endothermic transition at175° C. to 190° C., as measured by differential scanning calorimetry.28. The omecamtiv mecarbil free base crystalline form VI of claim 27,wherein the endothermic transition is at 185° C.±3° C.
 29. The omecamtivmecarbil free base crystalline form of claim 1, wherein the crystallineform is omecamtiv mecarbil free base crystalline form VII, characterizedby an X-ray powder diffraction (XRPD) pattern comprising peaks at 8.40,8.71, 13.08, 15.66, and 19.61±0.2° 2θ using Cu Kα radiation.
 30. Theomecamtiv mecarbil free base crystalline form VII of claim 29, furthercharacterized by XRPD pattern peaks at 4.37, 16.83, 18.92, 20.32, 20.49,22.26, 24.21, and 25.41±0.2° 2θ using Cu Kα radiation.
 31. The omecamtivmecarbil free base crystalline form VII of claim 29, furthercharacterized by XRPD pattern peaks at 7.84, 10.81, 21.61, 23.22, 23.46,27.58, 29.53, 30.13, and 31.32±0.2° 2θ using Cu Kα radiation.
 32. Theomecamtiv mecarbil free base crystalline form VII of claim 29, having anXRPD pattern substantially as shown in FIG. 12.